Pancreaticoduodenectomy (Whipple Resection)

Number: 0365

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References


Policy

Scope of Policy

This Clinical Policy Bulletin addresses pancreaticoduodenectomy (whipple resection).

  1. Medical Necessity

    Aetna considers the following interventions medically necessary:

    1. Pancreaticoduodenectomy (also known as Whipple resection) for the treatment of the following:
        1. Ampullary adenoma/carcinoma;
        2. Cholangiocarcinoma;
        3. Chronic pancreatitis;
        4. Combined pancreatic/duodenal injury;
        5. Duodenal neoplasm;
        6. Intraductal papillary mucinous neoplasm of the pancreas (IPMN) with high-grade dysplasia or invasive cancer;
        7. Neuroendocrine tumors;
        8. Pancreatic adenocarcinoma.

          Aetna considers pancreaticoduodenectomy (also known as Whipple resection or proximal pancreatectomy) experimental and investigational for the treatment of members with Zollinger-Ellison syndrome because the value of pancreaticoduodenectomy in this condition remains to be established. Furthermore, the morbidity and mortality related to this approach may outweigh its potential benefits.

      Note: Aetna considers the use of fibrin sealant integral to the pancreaticoduodenectomy procedure and not separately reimbursed. 

    2. Braun enteroenterostomy for lowering the incidence of delayed gastric emptying following pancreaticoduodenectomy;
    3. The use of pancreatic duct stents for the prevention of post-operative pancreatic fistula following pancreaticoduodenectomy.
  2. Experimental and Investigational

    Pre-operative biliary drainage and the use of omental flap for prevention of post-operative complications following pancreaticoduodenectomy are considered experimental and investigational because the effectiveness of these approaches has not been established.


Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code Code Description

Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":

Pancreaticoduodenectomy (also known as Whipple resection):

CPT codes covered if selection criteria are met:

48150 Pancreatectomy, proximal subtotal with total duodenectomy, partial gastrectomy, choledochoenterostomy and gastrojejunostomy (Whipple-type procedure); with pancreatojejunostomy
48152     without pancreatojejunostomy
48153 Pancreatectomy, proximal subtotal with near-total duodenectomy, choledochoenterostomy and duodenojejunostomy (pylorus-sparing, Whipple-type procedure); with pancreatojejunostomy
48154     without pancreatojejunostomy

CPT codes not covered for indications listed in the CPB:

49905 Omental flap, intra-abdominal (List separately in addition to code for primary procedure)

Other CPT codes related to the CPB:

47533 Placement of biliary drainage catheter, percutaneous, including diagnostic cholangiography when performed, imaging guidance (eg, ultrasound and/or fluoroscopy), and all associated radiological supervision and interpretation; external [not covered for prevention of complications]
47534 Placement of biliary drainage catheter, percutaneous, including diagnostic cholangiography when performed, imaging guidance (eg, ultrasound and/or fluoroscopy), and all associated radiological supervision and interpretation; internal-external [not covered for prevention of complications]
47535 Conversion of external biliary drainage catheter to internal-external biliary drainage catheter, percutaneous, including diagnostic cholangiography when performed, imaging guidance (eg, fluoroscopy), and all associated radiological supervision and interpretation [not covered for prevention of complications]
47536 Exchange of biliary drainage catheter (eg, external, internal-external, or conversion of internal-external to external only), percutaneous, including diagnostic cholangiography when performed, imaging guidance (eg, fluoroscopy), and all associated radiological supervision and interpretation [not covered for prevention of complications]

ICD-10 codes covered if selection criteria are met:

C17.0 Malignant neoplasm of duodenum
C22.1 Intrahepatic bile duct carcinoma
C24.0 Malignant neoplasm of extrahepatic bile duct
C24.1 Malignant neoplasm of ampulla of Vater
C25.0 - C25.9 Malignant neoplasm of pancreas
C7A.00 – C7B.8 Neuroendocrine tumors
D01.49 Carcinoma in situ of other parts of intestine
D01.5 Carcinoma in situ of liver, gallbladder and bile ducts
D13.2 Benign neoplasm of duodenum
D13.5 Benign neoplasm of extrahepatic bile ducts
D13.6 Benign neoplasm of pancreas
D13.7 Benign neoplasm of endocrine pancreas
D37.2 Neoplasm of uncertain behavior of small intestine
D37.6 Neoplasm of uncertain behavior of liver, gallbladder and bile ducts
D3A.010 Benign carcinoid tumor of the duodenum
D3A.8 Other benign neuroendocrine tumors
K86.0 Alcohol-induced chronic pancreatitis
K86.1 Other chronic pancreatitis
S36.200A - S36.299S Injury of pancreas
S36.400A - S36.400S Unspecified injury of duodenum
S36.410A - S36.410S Primary blast injury of duodenum
S36.420A - S36.420S Contusion of duodenum
S36.430A - S36.430S Laceration of duodenum
S36.490A - S36.490S Other injury of duodenum

ICD-10 codes not covered for indications listed in the CPB:

E16.4 Increased secretion of gastrin [Zollinger-Ellison syndrome]

Braun enteroenterostomy:

CPT codes covered if selection criteria are met:

44130 Enteroenterostomy, anastomosis of intestine, with or without cutaneous enterostomy (separate procedure) [Braun enteroenterostomy]

ICD-10 codes covered if selection criteria are met:

K91.89 Other postprocedural complications and disorders of digestive system [delayed gastric emptying following pancreaticoduodenectomy]

Fibrin sealant - no specific code:


Background

Zollinger-Ellison syndrome (ZES) is characterized by severe peptic ulcer disease that results from non-beta islet cell tumors, gastrinomas, of the gastrointestinal tract.  The mean age at presentation is 45 to 50 years, and men are affected more often than women.  Gastrinomas can be subdivided into tumors that are sporadic, constituting about 75 % of patients with ZES, and those that are genetically transmitted and associated with multiple endocrine neoplasia type 1 (MEN 1), constituting about 25 % of patients with ZES.  Zollinger-Ellison tumors associated with MEN-1 occur at an earlier age than the sporadic tumors and have been characterized by some researchers to follow a more benign course.

Currently, the literature states that proton-pump inhibitors (PPIs) such as lansoprazole (Prevacid) and omeprazole (Prilosec) are the treatment of choice for ZES.  For patients who have difficulty controlling gastric acid hyper-secretion with oral PPIs, intravenous pantoprazole (Protonix I.V.) has been reported to be effective.  Most ZES patients (93 %) maintained effective control of acid output previously established with oral PPIs when switched to twice-daily 80 mg of intravenously administered pantoprazole.  In patients with sporadic ZES, the literature suggests that exploratory surgery with tumor resection is also appropriate.  According to accepted guidelines, surgical resection of a single gastrinoma may be attempted if there is no evidence that it has spread to other organs (e.g., lymph nodes or the liver).  Gastrectomy to control acid over-production is rarely indicated.  However, the role of pancreaticoduodenectomy (Whipple resection, or proximal pancreatectomy) in patients with sporadic gastrinomas and in patients with MEN-1 is controversial.  Furthermore, the effect of aggressive surgery, such as the Whipple resection, on survival is unclear.

In a review on surgical treatment and prognosis of gastrinoma, Norton (2005) noted that Whipple pancreaticoduodenectomy results in the highest probability of cure in both sporadic and MEN-1 gastrinoma patients as it removes the entire gastrinoma triangle.  However, the excellent long-term survival of these patients with lesser operations and the increased operative mortality and long-term morbidity of Whipple pancreaticoduodenectomy make its current role unclear until further studies are done.

Bartsch et al (2007) stated that gastrinoma is the most frequent functional pancreaticoduodenal endocrine tumor in patients with MEN-1 and a major determinant of mortality in this syndrome.  Whether routine surgical exploration should be performed in patients with MEN-1 associated ZES to possibly decrease the malignant spread and eventually increase survival still remains controversial.  There is not only disagreement about the indication for surgical exploration, but also what type of procedure should be performed, since sufficient evidence-based data are not available.

In a review on surgical management of ZES, Morrow and Norton (2009) stated that much has been learned about the diagnosis and treatment of ZES, and certain questions require further investigation.  Delay in diagnosis of ZES is still a significant problem, and clinical suspicion should be elevated.  The single best imaging modality for localization and staging of ZES is somatostatin receptor scintigraphy.  Goals of surgical treatment for ZES differ between sporadic and MEN-1-related cases.  All sporadic cases of ZES should be surgically explored (including duodenotomy) even with negative imaging results, because of the high likelihood of finding and removing a tumor for potential cure.  Surgery for MEN-1-related cases should be focused on prevention of metastatic disease, with surgery being recommended when pancreatic tumors are greater than 2 cm.  The authors noted that the role of Whipple procedure, especially for MEN-1 cases, should be explored further.  Laparoscopic and endoscopic treatments are more experimental, but may have a role.

An UpToDate review on "Pancreaticoduodenectomy (Whipple procedure): Techniques" (Reber, 2013) does not mention Zollinger-Ellison syndrome as an indication of pancreaticoduodenectomy.  Furthermore, an UpToDate review on "Management and prognosis of the Zollinger-Ellison syndrome (gastrinoma)" (Goldfinger, 2013) does not mention pancreaticoduodenectomy as a therapeutic option.

Coolsen and colleagues (2014) stated that few randomized controlled trials (RCTs) have been performed in patients undergoing pancreatico-duodenectomy (PD).  An important factor contributing to this is the large number of patients needed to adequately power RCTs for relevant clinical single endpoints.  A PD-specific composite end-point (CEP) could solve this problem.  The aim of the present study was to develop a PD-specific CEP, consisting of complications related to PD, allowing reduction in sample sizes and improving the ability to compare outcomes.  PD-specific CEP components were selected after a systematic review of the literature and consensus between 25 international pancreatic surgeons.  Ultimately, prospective cohorts of patients who underwent PD in 2 high-volume HPB centers (London, UK, and Maastricht, NL) were used to assess the event rate and effect of implementing a PD-specific CEP.  From a total of 18 single-component end-points, 8 were selected to be included the PD-specific CEP:
  1. intra-abdominal abscess,
  2. sepsis,
  3. post-PD hemorrhage,
  4. bile leakage,
  5. gastro-jejunostomy leakage,
  6. leakage of the pancreatic anastomosis,
  7. delayed gastric emptying, and
  8. operative mortality within 90 days.
All 8 components had consensus definitions and a Dindo-Clavien classification of 3 or more.  The incidence of the PD-specific CEP was 24.7 % in the Maastricht cohort and 23.3 % in the London cohort.  These incidence rates led to a 2-fold reduction in the theoretical calculated sample size for an adequately powered RCT on PD using this CEP as a primary end-point.  The authors concluded that the proposed PD-specific CEP enables clinical investigators to adequately power RCTs on PD and increases the feasibility, comparability, and utility in meta-analysis.

Tenner et al (1996) stated that intraductal mucin-hypersecreting neoplasm (IMHN), also termed mucinous ductal ectasia, is a rare disorder of the pancreas characterized by distension of the pancreatic duct with mucus.  This study attempted to clarify the clinical, radiographic, histological, and treatment approaches to this entity.  The medical records, radiological imaging studies, and pathology specimens of 8 patients with IMHN seen during a 3-yr period were reviewed.  The diagnosis of IMHN was established by findings during ERCP, which included mucin plugging of the papilla, mucin extrusion from the papillary orifice after intraductal injection of contrast medium, mucinous filling defects in the main pancreatic duct, and dilated main and branch pancreatic ducts in the absence of obstructing ductal strictures.  All patients presented with an initial clinical diagnosis of acute or chronic pancreatitis, suspected cystic neoplasm, or biliary obstruction.  Non-invasive imaging studies such as trans-abdominal ultrasonography or CT and laboratory evaluation did not seem to help in defining the disease.  Five patients underwent Whipple resection; pathology included papillary ductal hyperplasia in 1, dysplastic mucinous epithelium in 2, and mucinous cystadenocarcinoma in 2.  All 5 patients had associated histological evidence of chronic pancreatitis.  All patients are alive and well after 21 to 53 months without evidence of residual disease.  The authors concluded that IMHN has a wide spectrum of clinical, radiological, and histological features.  The indolent biologic behavior and favorable prognosis of IMHN suggested that it is one of the most curable forms of pancreatic malignancy.

Paal et al (1999) noted that intraductal papillary-mucinous neoplasms (IPMNs) of the pancreas are rare lesions.  These researchers undertook this study to analyze these tumors by focusing on the diagnostic criteria and correlating the histologic features with clinical prognosis.  A total of 22 cases of IPMN were retrieved from the Endocrine Tumor Registry of the Armed Forces Institute of Pathology.  Blocks or unstained slides were available for histochemical and immunohistochemical studies (including proliferative markers and cell cycle regulators) and K-ras oncogene mutations in 15 cases.  Patient follow-up was obtained in all of the cases.  IPMN occurs in both genders with a slight male predominance, with a mean age at presentation of 64.4 years (range of 48 to 85 yrs).  The patients presented with abdominal pain.  The neoplasms were radiologically and grossly cystic, usually (18 cases of 22) located in the head of the pancreas.  Histologically, the tumors consisted of intraductal papillary proliferations protruding into and expanding the pancreatic ducts.  Invasion into the surrounding pancreatic parenchyma was detected in 15 cases.  Chronic pancreatitis was present in all of the cases.  p27 immunoreactivity always exceeded the immunoreactivity of cyclin E.  K-ras oncogene mutations were detected in 2 cases.  Patients were treated with a complete surgical resection (n = 7) or a Whipple procedure (n = 13).  Only 2 of 22 patients died of disease (3 died immediately post-operatively and 3 died of unrelated causes), whereas the remaining 14 patients were alive at last follow-up, without evidence of disease, an average of 58.2 months after initial presentation.  IPMNs are rare, distinctive neoplasms, with complex intraductal papillae, that can be easily separated from in-situ ductal adenocarcinoma and mucinous cystic neoplasms.  The high ratio of p27 protein to cyclin E supports the excellent prognosis of these neoplasms, despite the presence of invasion and K-ras oncogene mutation.

Fernandez-Cruz et al (2006) stated that the standard surgical procedure for IPMN of the main duct (IPMN-M) or side branch ducts (IPMN-Br) is pancreaticoduodenectomy.  IPMN-BR is a more indolent disease with a lower incidence of malignancy.  These investigators evaluated the usefulness of organ-preserving pancreatic resections (OPPR) including duodenum-preserving pancreatic head resection (DPHR) and pancreatic head resection with segmental duodenectomy (PHRSD) in patients with IPMN-BR.  Surgical outcomes were evaluated in 8 IPMN-Br patients: DPHR was performed in 4 patients and PHRSD was performed in 4 patients.  In addition, 13 IPMN patients with Whipple resections were included in the analysis.  The incidence of post-operative complications was 38 % after Whipple resection, 100 % after DPHR and 25 % after PHRSD.  The mean length of hospital stay was 27 days after DPHR, 22 days after Whipple resection and 16 days after PHRSD.  Invasive IPMN was found in 38 % of the patients in the Whipple group, and non-invasive IPMN was found in 100 % of patients who underwent organ-preserving surgery.  The authors concluded that pancreaticoduodenectomy remains the treatment of choice in patients with invasive IPMN.  PHRSD appears to be a useful procedure for IPMN-Br located in the head of the pancreas.

Beger et al (2013) stated that cystic neoplasms of the pancreas are being detected and surgically treated increasingly more frequently.  Intraductal papillary mucinous neoplasms and mucinous cystic neoplasms (MCN) are primary benign lesions; however, the 5-year risk for malignant transformation has been estimated to be 63 % and 15 %, respectively.  Surgical extirpation of a benign cystic tumor of the pancreas is a cancer preventive measure.  The duodenum-preserving total pancreatic head resection technique (DPPHRt) is being used more frequently for cystic neoplasms of the pancreatic head.  The complete resection of the pancreatic head can be applied as a duodenum-preserving technique or with segmental resection of the peri-papillary duodenum.  Borderline lesions, carcinoma in situ or T1N0 cancer of the papilla and the peri-papillary common bile duct are also considered to be indications for segmental resection of the peri-papillary duodenum.  A literature search for cystic neoplastic lesions and DPPHRt revealed the most frequent indications to be IPMN, MCN and SCA lesions and 28 % suffered from a cystic neoplasm with carcinoma in-situ or a peri-papillary malignoma.  The hospital mortality rate was 0.52 %.  Compared to the Whipple type resection the DPPHRt exhibits significant benefits with respect to a low risk for early post-operative complications and a low hospital mortality rate of less than 1 %.  Exocrine and endocrine pancreatic functions after DPPHR are not impaired compared to the Whipple type resection.

Aimoto et al (2013) investigated the clinicopathological features of borderline resectable invasive carcinomas (BRICs) derived from IPMNs and examined the significance of the aggressive "surgery first" approach compared with the treatment of conventional borderline resectable pancreatic ductal adenocarcinomas (BRPDAs).  These researchers retrospectively studied 7 patients with BRICs derived from IPMNs and 14 patients with conventional BRPDAs.  Several factors were reviewed: initial symptoms, pre-operative imaging, serum level of CA19-9, peri-operative factors, pathological findings, adjuvant chemotherapy, and outcome.  All BRICs derived from IPMN were huge tumors (more than 3 cm in diameter) suspected to involve less than 180° of the circumference of the vessel.  Five patients (71 %) underwent a modified Whipple procedure, and 2 (29 %) underwent distal pancreatectomy.  Only 3 patients (43 %) required vascular resection.  Curative resection was achieved in all 7 patients, who are alive with no evidence of recurrence.  There were no severe post-operative complications.  With regards to the pathological IPMN subtype, 2 tumors (29 %) were gastric and 5 (71 %) were intestinal.  Only 2 patients (29 %) had lymph node metastasis.  The final stage was II in 4 (57 %) cases and IVa in 3 cases (43 %).  The 3-year survival rate was 100 %.  Tumors of BRICs derived from IPMNs were larger than those of conventional BRPDAs (p < 0.05).  The BRICs derived from IPMN less frequently metastasized to lymph nodes (p < 0.05) and were of an earlier stage (p < 0.05) than were conventional BRPDAs.  The 3-year survival rate was significantly higher for BRICs derived from IPMNs (100 %) than for conventional BRPDAs (19 %, p < 0.001).  The authors concluded that the BRICs derived from an intestinal or gastric IPMN are less aggressive than conventional BRPDAs and have a more favorable prognosis. In addition, aggressive "surgery first" approach may contribute to this better prognosis.

Furthermore, an UpToDate review on "Diagnosis and treatment of intraductal papillary mucinous neoplasm of the pancreas" (Sheth et al, 2015) states that "Surgery is the only treatment option in patients with intraductal papillary mucinous neoplasm of the pancreas (IPMN) with high-grade dysplasia or invasive cancer …. Surgical series have described a variety of operations for IPMN, including total pancreatectomy, pancreaticoduodenectomy, distal pancreatectomy, and segmental resection of the tumor.  The choice of surgery will be determined by the location of the tumor and the extent of involvement of the gland …. The most common operation is pancreaticoduodenectomy (70 %) because most tumors are in the head of the pancreas".

In a meta-analysis, Chen et al (2015a) analyzed the morbidity after pylorus-preserving pancreaticoduodenectomy (PPPD) and pylorus-resecting pancreaticoduodenectomy (PRPD) to determine the optimal surgical treatment of masses in the pancreatic head or peri-ampullary region.  A systematic search of databases identifying RCTs from the Cochrane Library, PubMed, EMBASE and Web of Science was performed.  Outcome was compared by post-operative morbidity including overall morbidity, pancreatic fistulas, wound infections, post-operative bleeding, biliary leakage, ascites and delayed gastric emptying (DGE) rate between PPPD and PRPD.  The DGE rate in the PRPD subgroups (conventional PD [CPD] and subtotal stomach-preserving PD [SSPPD], respectively) was also analyzed.  The results showed that 9 RCTs including 722 participants were included for meta-analysis.  Among these RCTs, 7 manuscripts described PRPD as CPD, and 2 manuscripts described PRPD as SSPPD.  There were no significant differences in the overall morbidity, pancreatic fistulas, wound infections, post-operative bleeding, or biliary leakage between PPPD and PRPD.  There was a lower rate of DGE with PRPD than that with PPPD (relative risk [RR] = 2.15, p = 0.03, 95 % confidence interval [CI]: 1.09 to 4.23).  Further subgroup analysis indicated a comparable DGE rate for the CPD but a lower DGE rate for the SSPPD group than the PPPD group.  However, the result did not indicate any difference between CPD and SSPPD regarding the DGE rate (p = 0.92).  It is suggested that PPPD is comparable to PRPD in overall morbidity, pancreatic fistulas, wound infections, post-operative bleeding and biliary leakage.  The authors concluded that the current data are insufficient to draw a conclusion regarding which surgical procedure is associated with a lower post-operative DGE rate; these conclusions were limited by the available data.  They stated that further evaluations of RCTs are needed.

In a Cochrane review, Huttner et al (2016) compared the effectiveness of classic Whipple (CW) operation (pancreaticoduodenectomy) and pylorus-preserving pancreaticoduodenectomy (PPW) techniques for surgical treatment of cancer of the pancreatic head and the peri-ampullary region.  These researchers conducted searches on March 28, 2006, January 11, 2011, January 9, 2014, and August 18, 2015 to identify all RCTs, while applying no language restrictions.  They searched the following electronic databases on August 18, 2015: the Cochrane Central Register of Controlled Trials (CENTRAL), the Cochrane Database of Systematic Reviews (CDSR) and the Database of Abstracts of Reviews of Effects (DARE) from the Cochrane Library (2015, Issue 8); MEDLINE (1946 to August 2015); and EMBASE (1980 to August 2015).  They also searched abstracts from Digestive Disease Week and United European Gastroenterology Week (1995 to 2010); they did not update this part of the search for the 2014 and 2015 updates because the prior searches did not contribute any additional information.  These investigators identified 2 additional trials through the updated search in 2015; RCTs comparing CW versus PPW including participants with peri-ampullary or pancreatic carcinoma were selected for analysis.  Two review authors independently extracted data from the included trials.  They used a random-effects model for pooling data.  They compared binary outcomes using odds ratios (ORs), pooled continuous outcomes using mean differences (MDs), and used hazard ratios (HRs) for meta-analysis of survival.  Two review authors independently evaluated the methodological quality and risk of bias of included trials according to the standards of the Cochrane Collaboration.  These researchers included 8RCTs with a total of 512 participants.  The critical appraisal revealed vast heterogeneity with respect to methodological quality and outcome parameters.  Post-operative mortality (OR 0.64, 95 % CI: 0.26 to 1.54; p = 0.32), overall survival (HR 0.84, 95 % CI: 0.61 to 1.16; p = 0.29), and morbidity showed no significant differences, except of delayed gastric emptying, which significantly favored CW (OR 3.03, 95 % CI: 1.05 to 8.70; p = 0.04).  Furthermore, these investigators noted that operating time (MD -45.22 minutes, 95 % CI: -74.67 to -15.78; p = 0.003), intra-operative blood loss (MD -0.32 L, 95 % CI: -0.62 to -0.03; p = 0.03), and red blood cell transfusion (MD -0.47 units, 95 % CI: -0.86 to -0.07; p = 0.02) were significantly reduced in the PPW group.  All significant results were associated with low-quality evidence based on GRADE (Grades of Recommendation, Assessment, Development and Evaluation) criteria.  The authors concluded that current evidence suggested no relevant differences in mortality, morbidity, and survival between the 2 operations.  However, some peri-operative outcome measures significantly favored the PPW procedure.  Given obvious clinical and methodological heterogeneity, future high-quality RCTs of complex surgical interventions based on well-defined outcome parameters are needed.

In a Cochrane review, Gurusamy et al (2016) evaluated the benefits and harms of duodenum-preserving pancreatic head resection (DPPHR) versus PD in people with chronic pancreatitis for whom pancreatic resection is considered the main therapeutic option.  These investigators searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Science Citation Index Expanded, and trials registers to June 2015 to identify randomized trials.  They also searched the references of included trials to identify further trials.  They considered only RCT performed in people with chronic pancreatitis undergoing pancreatic head resection, irrespective of language, blinding, or publication status, for inclusion in the review.  Two review authors independently identified trials and extracted data.  They calculated the RR, MD, rate ratio (RaR), or HR with 95 % CI based on an available-case analysis.  A total of 5 trials including 292 participants met the inclusion criteria for the review.  After exclusion of 23 participants mainly due to pancreatic cancer or because participants did not receive the planned treatment, a total of 269 participants (with symptomatic chronic pancreatitis involving the head of pancreas and requiring surgery) were randomly assigned to receive DPPHR (135 participants) or PD (134 participants).  The trials did not report the American Society of Anesthesiologists (ASA) status of the participants.  All the trials were single-center trials and included people with and without obstructive jaundice and people with and without duodenal stenosis, but did not report data separately for those with and without jaundice or those with and without duodenal stenosis.  The surgical procedures compared in the 5 trials included DPPHR (Beger or Frey procedures, or wide local excision of the head of the pancreas) and PD (pylorus-preserving pancreaticoduodenectomy or Whipple procedure).  The participants were followed-up for various periods of time ranging from 1 to 15 years.  The trials were at unclear or high risk of bias.  The overall quality of evidence was low or very low.  The differences in short-term mortality (up to 90 days after surgery) (RR 2.89, 95 % CI: 0.31 to 26.87; 369 participants; 5 studies; DPPHR: 2/135 (1.5 %) versus PD: 0/134 (0 %); very low quality evidence) or long-term mortality (maximal follow-up) (HR 0.65, 95 % CI: 0.31 to 1.34; 229 participants; 4 studies; very low quality evidence), medium-term (3 months to 5 years) (only a narrative summary was possible; 229 participants; 4 studies; very low quality evidence), or long-term quality of life (more than five years) (MD 8.45, 95% CI -0.27 to 17.18; 101 participants; 2 studies; low quality evidence), proportion of people with adverse events (RR 0.55, 95% CI 0.22 to 1.35; 226 participants; 4 studies; DPPHR: 23/113 (adjusted proportion 20 %) versus PD: 41/113 (36.3 %); very low quality evidence), number of people with adverse events (RaR 0.95, 95 % CI: 0.43 to 2.12; 43 participants; 1 study; DPPHR: 12/22 (54.3 events per 100 participants) versus PD: 12/21 (57.1 events per 100 participants); very low quality evidence), proportion of people employed (maximal follow-up) (RR 1.54, 95 % CI: 1.00 to 2.37; 189 participants; 4 studies; DPPHR: 65/98 (adjusted proportion 69.4 %) versus PD: 41/91 (45.1 %); low quality evidence), incidence proportion of diabetes mellitus (maximum follow-up) (RR 0.78, 95 % CI: 0.50 to 1.22; 269 participants; 5 studies; DPPHR: 25/135 (adjusted proportion 18.6 %) versus PD: 32/134 (23.9 %); very low quality evidence), and prevalence proportion of pancreatic exocrine insufficiency (maximum follow-up) (RR 0.83, 95 % CI: 0.68 to 1.02; 189 participants; 4 studies; DPPHR: 62/98 (adjusted proportion 62.0 %) versus PD: 68/91 (74.7 %); very low quality evidence) were imprecise.  The length of hospital stay appeared to be lower with DPPHR compared to PD and ranged between a reduction of 1 day and 5 days in the trials (208 participants; 4 studies; low quality evidence). None of the trials reported short-term quality of life (4 weeks to 3 months), clinically significant pancreatic fistulas, serious adverse events, time to return to normal activity, time to return to work, and pain scores using a visual analog scale.  The authors concluded that low quality evidence suggested that DPPHR may result in shorter hospital stay than PD.  Based on low or very low quality evidence, there is currently no evidence of any difference in the mortality, adverse events, or quality of life between DPPHR and PD.  However, the results were imprecise and further RCTs are needed on this topic.  They stated that future RCTs comparing DPPHR with PD should report the severity as well as the incidence of post-operative complications and their impact on patient recovery. In such trials, participant and observer blinding should be performed and the analysis should be performed on an intention-to-treat basis to decrease the bias.  In addition to the short-term benefits and harms such as mortality, surgery-related complications, quality of life, length of hospital stay, return to normal activity, and return to work, future trials should consider linkage of trial participants to health databases, social databases, and mortality registers to obtain the long-term benefits and harms of the different treatments.

Preoperative Biliary Drainage on Complications Following Pancreatoduodenectomy

In a meta-analysis, Chen et al (2015b) examined the impact of preoperative biliary drainage (PBD) on complications following PD.  A meta-analysis was carried out for all relevant RCTs, prospective and retrospective studies published from inception to March 2015 that compared PBD and non-PBD (immediate surgery) for the development of post-operative complications in PD patients.  Pooled odds ratio (OR) and 95 % CI were estimated using fixed-effect analyses, or random-effects analyses if there was statistically significant heterogeneity (p < 0.05).  A total of 8 RCTs, 13 prospective studies, 20 retrospective studies, and 3 Chinese local retrospective studies with 6,286 patients were included in this study.  In a pooled analysis, there were no significant differences between PBD and non-PBD group in the risks of mortality, morbidity, intra-abdominal abscess, sepsis, hemorrhage, pancreatic leakage, and biliary leakage.  However, subgroup analysis of RCTs yielded a trend toward reduced risk of morbidity in PBD group (OR 0.48, CI: 0.24 to 0.97; p = 0.04).  Compared with non-PBD, PBD was associated with significant increase in the risk of infectious complication (OR 1.52, CI: 1.07 to 2.17; p = 0.02), wound infection (OR 2.09, CI: 1.39 to 3.13; p = 0.0004), and DGE (OR 1.37, CI: 1.08 to 1.73; p = 0.009).  The authors concluded that the findings of this meta-analysis suggested that biliary drainage before PD increased post-operative infectious complication, wound infection, and DGE.  They stated that in light of these findings, PBD probably should not be routinely carried out in PD patients.

The Use of Omental Flap for Prevention of Complications Following Pancreaticoduodenectomy

In a meta-analysis, Tian et al (2015) examined the effect of omental flap in PD against post-operative complication.  Thorough literature search in Ovid-MEDLINE and EMBASE databases was conducted to identify studies whether the use of Omental Flap to prevent post-operative complications.  Review of 14 article candidates, identified 4 eligible articles with a total of 2,971 patients for meta-analysis.  Dichotomous data regarding distinction between omental roll-up and non-mental roll-up were pooled using random effects model to obtain the diagnostic ORs and their 95 % CIs.  There were a total of 1,129 patients in omental roll-up group, 1,842 patients in non-omental group.  Omental roll-up during PD could not prevent post-operative pancreatic fistula (OR = 0.81, 95 % CI: 0.40 to 1.63, p = 0.56).  it also could not prevent post-operative intra-abdominal bleeding (OR = 0.67, 95 % CI: 0.28 to 1.59, p = 0.37).  These researchers used the sensitivity analysis that found the pancreatic fistula was lower in the non-omental roll-up group than in the omental roll-up group (OR = 1.24, 95 % CI: 1.03 to 1.50, p = 0.02).  The authors concluded that the use of omental roll-up could not decrease the risk of pancreatic fistula after PD.  They stated that further RCTs are needed to identify the effect of omental roll-up technique for PD.

Minimally Invasive Pancreaticoduodenectomy for Peri-Ampullary Disease

Chen and colleagues (2017) stated that minimally invasive pancreatoduodenectomy (MIPD) has been gradually attempted.  However, whether MIPD is superior, equal or inferior to its conventional open pancreatoduodenectomy (OPD) is unclear.  These investigators performed a comprehensive review of literature and meta-analysis of MIPD outcomes compared with open surgery.  Studies published up to May 2017 were searched in PubMed, Embase, Cochrane Library, and Web of Science.  Main outcomes were comprehensively reviewed and measured including conversion to open approach, operation time (OP), estimated blood loss (EBL), transfusion, length of hospital stay (LOS), overall complications, post-operative pancreatic fistula (POPF), delayed gastric emptying (DGE), post-pancreatectomy hemorrhage (PPH), re-admission, re-operation and reasons of pre-operative death, number of retrieved lymph nodes (RLN), surgical margins, recurrence, and survival.  The software of Review Manage version 5.1 was used for meta-analysis.  A total of 100 studies were included for systematic review and 26 (a total of 3,402 cases, 1,064 for MIPD, 2,338 for OPD) were included for meta-analysis.  In the early years, most articles were case reports or non-control case series studies, while in the last 6 years high-volume and comparative researches were increasing gradually.  Systematic review revealed conversion rates of MIPD to OPD ranged from 0 % to 40 %.  The mean or median OP of MIPD ranged from 276 to 657 mins.  The total POPF rates vary between 3.8 % and 50 % observed in all systematic reviewed studies.  Meta-analysis demonstrated MIPD had longer OP (weighted mean difference [WMD] = 99.4 mins; 95 % CI: 46.0 to 152.8, p < 0.01), lower blood loss (WMD = -0.54 ml; 95 % CI: -0.88 to -0.20 ml; p < 0.01), lower transfusion rate (RR = 0.73, 95 % CI: 0.57 to 0.94, p = 0.02), shorter LOS (WMD = -3.49 days; 95 %CI: -4.83 to -2.15, p < 0.01).  There was no significant difference in time to oral intake, post-operative complications, POPF, re-operation, re-admission, peri-operative mortality and number of retrieved lymph nodes.  The authors concluded that the findings of this study demonstrated that MIPD was technically feasible and safe on the basis of historical studies; MIPD was associated with less blood loss, faster post-operative recovery, shorter length of hospitalization and longer operation time.  Moreover, they stated that these findings need to be confirmed with robust prospective comparative studies and randomized clinical trials.

In a systematic review and meta-analysis, Wang and associates (2017) evaluated the feasibility and safety of MIPD versus OPD.  Post-operative complications, intra-operative outcomes and oncologic data, and post-operative recovery were compared.  There were 27 studies that matched the selection criteria.  A total of 1,306 cases of MIPD and 5,603 cases of OPD were included; MIPD was associated with a reduction PPH (OR 1.60; 95 % CI: 1.03 to 2.49; p  = 0.04) and wound infection (OR 0.44, 95 % CI: 0.30 to 0.66, p < 0.0001).  MIPD was also associated with less EBL (mean difference [MD] -300.14 ml, 95 % CI: -400.11 to -200.17 ml, p  < 0.00001), a lower transfusion rate (OR 0.46, 95 % CI: 0.35 to 0.61; p < 0.00001) and a shorter LOS (MD -2.95 days, 95 % CI: -3.91 to -2.00 days, p  < 0.00001) than OPD.  Meanwhile, the MIPD group had a higher R0 resection rate (OR 1.45, 95 % CI: 1.18 to 1.78, p = 0.0003) and more RLN (MD 1.34, 95 % CI: 0.14 to 2.53, p  = 0.03).  However, the minimally invasive approach proved to have much longer OP (MD 71.00 mins; 95 % CI: 27.01 to 115.00 mins; p  = 0.002) than OPD.  Finally, there were no significant differences between the 2 procedures in POPF (p = 0.30), DGE (p  = 0.07), bile leakage (p = 0.98), mortality (p = 0.88), tumor size (p = 0.15), vascular resection (p = 0.68), or re-operation rate (p  = 0.11).  The authors concluded that these findings suggested that MIPD was safe, feasible, and worthwhile.  Moreover, they stated that future large, well-designed RCTs with extensive follow-up are needed to further clarify this role.

Kendrick and co-workers (2017) conducted an assessment of the best-evidence and expert opinion on the current status and future challenges of MIPD.  These investigators performed a systematic review of the literature and best-evidence on minimally invasive pancreatic resection.  Expert panel discussion and audience response activity was used to assess perceived value and future direction.  From 582 studies, 26 comparative trials of MIPD and OPD were assessed for peri-operative outcomes.  There were no RCTs and all available comparative studies were determined of low quality.  Several observational and case-matched studies demonstrated longer operative times, but less EBL and shorter LOS for MIPD.  Registry-based studies demonstrated increased mortality rates after MIPD in low-volume centers.  Oncologic assessment demonstrated comparable outcomes of MIPD.  Expert opinion supports ongoing evaluation of MIPD.  The authors concluded that MIPD appeared to provide similar peri-operative and oncologic outcomes in selected patients, when performed at experienced, high-volume centers.  Moreover, they stated that the overall role of MIPD in pancreatoduodenectomy needs to be better defined.  Improved training opportunities, registry participation and prospective evaluation are needed.

Pedziwiatr and colleagues (2017) compared MIPD versus OPD by using meta-analytical techniques.  Medline, Embase, and Cochrane Library were searched for eligible studies.  Data from included studies were extracted for the following outcomes: operative time, overall morbidity, pancreatic fistula, delayed gastric emptying, blood loss, post-operative hemorrhage, yield of harvested lymph nodes, R1 rate, length of hospital stay, and re-admissions.  Random and fix effect meta-analyses were undertaken.  Initial reference search yielded 747 articles.  Thorough evaluation resulted in 12 papers, which were analyzed.  The total number of patients was 2,186 (705 in MIPD group and 1,481 in OPD).  Although there were no differences in overall morbidity between groups, these researchers noticed reduced blood loss, DGE, and LOS in favor of MIPD.  In contrary, meta-analysis of operative time revealed significant differences in favor of open procedures.  Remaining parameters did not differ among groups.  The authors concluded that he findings of this meta-analysis suggested that although MIPD took longer, it may be associated with reduced blood loss, shortened LOS, and comparable rate of peri-operative complications.  Moreover, they stated that due to heterogeneity of included studies and differences in baseline characteristics between analyzed groups, the analysis of short-term oncological outcomes did not allow drawing unequivocal conclusions.  These researchers stated that the existing evidence for the use of laparoscopic surgery in pancreatic head malignancy is very limited and should be interpreted with caution; this supports the concept that further, better quality studies are needed to provide higher level of evidence on the benefits of minimally invasive approach in pancreatic head surgery.

Braun Enteroenterostomy for Lowering the Incidence of Delayed Gastric Emptying Following Pancreaticoduodenectomy

In a prospective RCT, Hwang and associates (2016) examined the clinical impact of Braun anastomosis on delayed gastric emptying (DGE) after pylorus-preserving PD (PPPD).  From February 2013 to June 2014, a total of 60 patients were recruited for this study.  The incidence of DGE and its risk factors were analyzed according to whether or not Braun anastomosis was used after PPPD; 30 patients were respectively enrolled in No-Braun group and Braun group.  A comparative analysis between the 2 groups showed no differences in sex, diagnosis, operation time, hospital stay, or post-operative complications, including pancreatic fistula.  Overall DGE developed in 8 patients (26.7 %) in the Braun group and in 14 patients (46.7 %) in the No-Braun group (p = 0.108).  However, clinically relevant DGE (grades B and C) was marginally more frequent in the No-Braun group (23.3 % versus 3.3 %, p = 0.052).  In a multi-variable analysis, No-Braun anastomosis was an independent risk factor for developing clinically relevant DGE (OR = 16.489; 95 % CI: 1.287 to 211.195; p = 0.031).  The authors concluded that the overall DGE occurrence was not different between the 2 groups.  However, No-Braun anastomosis was an independent risk factor for developing clinically relevant DGE.

The authors noted that this study had several limitations.  One drawback was the small number of patients (n = 60).  According to the reference study's result (i.e., the difference in DGE incidence rates between the Braun and No‐Braun groups was 30.8 %), the calculated sample size was small.  However, in order to avoid unnecessary randomization, these researchers tried to limit the sample size to the minimum needed for statistical analysis.  It was expected that a larger RCT will be conducted based on the current encouraging data to prove the beneficial effect of the Braun anastomosis for reducing clinically relevant DGE following PPPD.  In addition, it was interesting to note that, even though this study was designed as an RCT, approximately 40 % of eligible patients did not agree with enrollment.  As patients' awareness regarding the potential risks and ethical issues of RCTs is increasing, patients appeared hesitant to get actively involved in them.  This issue needs to be considered in planning future RCTs.  If effective patient's enrollment were not feasible, the power of the RCT may be limited, and even randomization would not be possible.

In a meta-analysis, Zhou and colleagues (2018) evaluated the impact of Braun enteroenterostomy on DGE following PD.  These investigators carried out a systematic review of the literature to identify relevant studies.  Statistical analysis was performed using Review Manager software 5.3.  A total of 11 studies involving 1,672 patients (1,005 in Braun group and 667 in non-Braun group) were included in the meta-analysis.  Braun enteroenterostomy was associated with a statistically significant reduction in overall DGE (OR 0.32, 95 % CI: 0.24 to 0.43; p < 0.001), clinically significant DGE (OR 0.27, 95 % CI: 0.15 to 0.51; p < 0.001), bile leak (OR 0.50, 95 % CI: 0.29 to 0.86; p = 0.01), and LOS (WMD -1.66, 95 % CI: -2.95 to 00.37; p = 0.01).  The authors concluded that Braun enteroenterostomy minimized the rate and severity of DGE following PD.  Moreover, these researchers stated that more larger-size RCTs are needed to confirm these findings.

The authors stated that this study had several  drawbacks.  First, significant statistical heterogeneity was detected between studies for some outcomes including the analysis of clinically significant DGE (I2 = 55 %), largely due to the fact that there were significant variations in each clinical setting regarding surgical technique and peri-operative care.  Second, the level of evidence was low, for a considerable number of data came from non-RCTs, knowing that non-RCTs have inherent risk of bias.  Finally, long-term outcomes such as the nutritional status were not analyzed in this meta-analysis due to the limited data. 

Use of Fibrin Sealant Patch for Reducing the Occurrence of Post-Operative Pancreatic Fistula and Complications Following Pancreaticoduodenectomy

Schindl and colleagues (2018) stated that the potential for a fibrin sealant patch to reduce the risk of post-operative pancreatic fistula (POPF) remains uncertain.  In a multi-center study, these researchers examined if a fibrin sealant patch is able to reduce POPF in patients undergoing PD with pancreatojejunostomy.  Subjects undergoing PD were randomized to receive either a fibrin patch (patch group) or no patch (control group), and stratified by gland texture, pancreatic duct size and neoadjuvant treatment.  The primary end-point was POPF; secondary end-points included complications, drain-related factors and LOS.  Risk factors for POPF were identified by logistic regression analysis.  A total of 142 patients were enrolled; 45 of 71 patients (63 %) in the patch group and 40 of 71 (56 %) in the control group developed biochemical leakage or POPF (p = 0.392).  Fistulas were classified as grade B or C in 16 (23 %) and 10 (14 %) patients, respectively (p = 0.277).  There were no differences in post-operative complications (54 patients in patch group and 50 in control group; p = 0.839), drain amylase concentration (p = 0.494), time until drain removal (mean (S.D.) 11.6 (1.0) versus 13.3 (1.3) days; p = 0.613), fistula closure (17.6 (2.2) versus 16.5 (2.1) days; p = 0.740) and LOS (22.1 (2.2) versus 18.2 (0.9) days; p = 0.810) between the 2 groups.  Multi-variable logistic regression analysis confirmed that obesity (OR 5.28, 95 % CI: 1.20 to 23.18; p = 0.027), soft gland texture (OR 9.86, 95 % CI: 3.41 to 28.54; p < 0.001) and a small duct (OR 5.50, 1.84 to 16.44; p = 0.002) were significant risk factors for POPF.  A patch did not reduce the incidence of POPF in patients at higher risk.  The authors concluded that the use of a fibrin sealant patch did not reduce the occurrence of POPF and complications after PD with pancreatojejunostomy.

In a Cochrane review, Gong and associates (2018) examined  the safety, effectiveness, and potential adverse effects of fibrin sealants for the prevention of POPF following pancreatic surgery.  These investigators searched trial registers and the following biomedical databases: the Cochrane Library (2018, Issue 4), Medline (1946 to April 12, 2018), Embase (1980 to April 12, 2018), Science Citation Index Expanded (1900 to April 12, 2018), and Chinese Biomedical Literature Database (CBM) (1978 to April 12, 2018).  They included all RCTs that compared fibrin sealant (fibrin glue or fibrin sealant patch) versus control (no fibrin sealant or placebo) in people undergoing pancreatic surgery.  Two review authors independently identified the trials for inclusion, collected the data, and assessed the risk of bias.  They performed the meta-analyses using Review Manager 5, calculated the RR for dichotomous outcomes (or a Peto OR for very rare outcomes), and the MD for continuous outcomes, with 95 % CIs.  These researchers included 11 studies involving 1,462 subjects in the review.  Application of fibrin sealants to pancreatic stump closure reinforcement after distal pancreatectomy:  They included 7 studies involving 860 participants: 428 were randomized to the fibrin sealant group and 432 to the control group after distal pancreatectomy.  Fibrin sealants may lead to little or no difference in POPF (fibrin sealant 19.3 %; control 20.1 %; RR 0.96, 95 % CI: 0.68 to 1.35; 755 participants; 4 studies; low-quality evidence).  Fibrin sealants may also lead to little or no difference in post-operative mortality (0.3 % versus 0.5 %; Peto OR 0.52, 95 % CI: 0.05 to 5.03; 804 participants; 6 studies; low-quality evidence), or overall post-operative morbidity (28.5 % versus 23.2 %; RR 1.23, 95 % CI: 0.97 to 1.58; 646 participants; 3 studies; low-quality evidence).  The authors were uncertain whether fibrin sealants reduced re-operation rate (2.0 % versus 3.8 %; RR 0.51, 95 % CI: 0.15 to 1.71; 376 participants; 2 studies; very low-quality evidence).  There was probably little or no difference in LOS between the groups (12.1 days versus 11.4 days; MD 0.32 days, 95 % CI: -1.06 to 1.70; 755 participants; 4 studies; moderate-quality evidence).  The studies did not report serious adverse events (AEs), quality of life (QOL), or cost-effectiveness.  Application of fibrin sealants to pancreatic anastomosis reinforcement after PD: These investigators included 3 studies involving 251 participants: 115 were randomized to the fibrin sealant group and 136 to the control group after PD.  They were uncertain whether fibrin sealants reduced POPF (1.6 % versus 6.2 %; RR 0.25, 95 % CI: 0.01 to 5.06; 57 participants; 1 study; very low-quality evidence).  Fibrin sealants may lead to little or no difference in post-operative mortality (0.1 % versus 0.7 %; Peto OR 0.15, 95 % CI: 0.00 to 7.76; 251 participants; 3 studies; low-quality evidence) or LOS (12.8 days versus 14.8 days; MD -1.58 days, 95 % CI: -3.96 to 0.81; 181 participants; 2 studies; low-quality evidence).  These researchers were uncertain whether fibrin sealants reduced overall post-operative morbidity (33.7 % versus 34.7 %; RR 0.97, 95 % CI: 0.65 to 1.45; 181 participants; 2 studies; very low-quality evidence), or re-operation rate (7.6 % versus 9.2 %; RR 0.83, 95 % CI: 0.33 to 2.11; 181 participants; 2 studies, very low-quality evidence).  The studies did not report serious AEs, QOL, or cost-effectiveness.  Application of fibrin sealants to pancreatic duct occlusion after PD: These investigators  included 2 studies involving 351 participants: 188 were randomized to the fibrin sealant group and 163 to the control group after PD.  Fibrin sealants may lead to little or no difference in post-operative mortality (8.4 % versus 6.1 %; Peto OR 1.41, 95 % CI: 0.63 to 3.13; 351 participants; 2 studies; low-quality evidence) or LOS (17.0 days versus 16.5 days; MD 0.58 days, 95 % CI: -5.74 to 6.89; 351 participants; 2 studies; low-quality evidence).  They were uncertain whether fibrin sealants reduced overall post-operative morbidity (32.0 % versus 27.6 %; RR 1.16, 95 % CI: 0.67 to 2.02; 351 participants; 2 studies; very low-quality evidence), or re-operation rate (13.6 % versus 16.0 %; RR 0.85, 95 % CI: 0.52 to 1.41; 351 participants; 2 studies; very low-quality evidence).  Serious AEs were reported in 1 study: more participants developed diabetes mellitus when fibrin sealants were applied to pancreatic duct occlusion, both at 3 months' follow-up (33.7 % fibrin sealant group versus 10.8 % control group; 29 participants versus 9 participants) and 12 months' follow-up (33.7 % fibrin sealant group versus 14.5 % control group; 29 participants versus 12 participants).  The studies did not report POPF, QOL, or cost-effectiveness.  The authors concluded that based on the current available evidence, fibrin sealants may have little or no effect on POPF in people undergoing distal pancreatectomy.  Moreover, these investigators stated that the effects of fibrin sealants on the prevention of POPF are uncertain in people undergoing PD.

Pancreatic Duct Stents for Post-Operative Pancreatic Fistula Following Pancreaticoduodenectomy

Jiang and colleagues (2021) noted that there is no specific evidence regarding the benefits of external and internal pancreatic duct stents following PD since pancreatic fistula (grade A) have been re-defined with no clinical treatment effect.  These investigators re-examined the prognostic value of external and internal stents in clinically relevant post-operative pancreatic fistula following PD.  PubMed, Web of Science, Embase and the Cochrane Database were specifically searched for pertinent and original articles published before May 2019.  The project has been registered in PROSPERO (Registration number: CRD42019137579).  A total of 4 RCTs and 6 non-RCTs with a total of 2,101 patients were enrolled in this meta-analysis.  The use of an external stent resulted in better performance than the use of an internal stent in terms of pancreatic fistula (grade C) (OR 0.58, p = 0.03); but did not reduce the rate of pancreatic fistula (grade B) (OR 0.99, p = 0.94) in all studies.  The meta-analysis of RCTs found that the use of an external stent approached a level of significance for an increased rate of clinically relevant post-operative pancreatic fistula compared to the use of an internal stent (OR 1.40, p = 0.10); but had no significant effect on pancreatic fistula (grade B) (OR 1.34, p = 0.26) or pancreatic fistula (grade C) (OR 1.68, p = 0.62).  The authors concluded that compared with internal stents, the use of external stent might be associated with a lower rate of pancreatic fistula (grade C).  Moreover, these researchers stated that more randomized clinical trials are needed to further examine the safety and efficacy of pancreatic duct external stents.

An UpToDate review (Reber, 2020) noted that "Placement of a pancreatic stent has the potential to decompress the main pancreatic duct and provide drainage of pancreatic secretions. However, the role of pancreatic stents in preventing pancreatic fistula is unclear. Available studies have important methodologic limitations. Until sufficient evidence is available, pancreatic stenting as a means to prevent postoperative pancreatic fistula following pancreaticoduodenectomy is according to surgeon preference."  The UpToDate review noted that at least eight randomized trials have been conducted to investigate the role of pancreatic stenting in pancreaticoduodenectomy. An additional five randomized trials are ongoing, the results of which have not been reported. 

In a Cochrane review, Dong et al (2016) conducted a metaanalysis of randomized trials to determine the efficacy of pancreatic stents in preventing pancreatic fistula after pancreaticoduodenectomy. The investigators searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Web of Science, and four major Chinese biomedical databases up to November 2015. They also searched several major trials registers. The investigators included randomized controlled trials (RCTs) comparing the use of stents (either internal or external) versus no stents, and comparing internal stents versus external stents, replacement versus no replacement following pancreaticoduodenectomy. Two review authors independently extracted the data. The outcomes studied were incidence of pancreatic fistula, need for reoperation, length of hospital stay, overall complications, and in-hospital mortality. They calculated the results as risk ratio (RR) or mean difference (MD), with 95% confidence interval (CI). They assessed the quality of evidence using GRADE. The investigators included eight studies (1018 participants). The average age of the participants ranged from 56 to 68 years. Most of the studies were conducted in single centers in Japan (four studies), China (two studies), France (one study), and the USA (one study). The risk of bias was low or unclear for most domains across the studies. The effect of stents on reducing pancreatic fistula in people undergoing pancreaticoduodenectomy was uncertain due to the low quality of the evidence (RR 0.67, 95% CI 0.39 to 1.14; 605 participants; 4 studies). The risk of in-hospital mortality was 3% in people who did receive stents compared with 2% (95% CI 1% to 6%) in people who had stents (RR 0.73, 0.28 to 1.94; 605 participants; 4 studies; moderate-quality evidence). The effect of stents on reoperation was uncertain due to wide confidence intervals (RR 0.67, 0.36 to 1.22; 512 participants; 3 studies; moderate-quality evidence). They found moderate-quality evidence that using stents  reduces total hospital stay by just under four days (mean difference (MD) -3.68, 95% CI -6.52 to -0.84; 605 participants; 4 studies). The risk of delayed gastric emptying, wound infection, and intra-abdominal abscess was uncertain (gastric emptying: RR 0.75, 95% CI 0.24 to 2.35; moderate-quality evidence) (wound infection: RR 0.73, 95% CI 0.40 to 1.32; moderate-quality evidence) (abscess: RR  1.38, 0.49 to 3.85; low-quality evidence). Subgroup analysis by type of stent provided limited evidence that external stents lead to lower risk of fistula compared with internal stents. The effect of external stents on the risk of pancreatic fistula, reoperation, delayed gastric emptying, and intra-abdominal abscess compared with internal stents was uncertain due to low-quality evidence (fistula: RR 1.44, 0.94 to 2.21; 362 participants; 3 studies) (reoperation: RR 2.02, 95% CI 0.38 to 10.79; 319 participants; 3 studies) (gastric emptying: RR 1.65, 0.66 to 4.09; 362 participants; 3 studies) (abscess: RR 1.91, 95% CI 0.80 to 4.58; 362 participants; 3 studies). The rate of in-hospital mortality was lower in studies comparing internal and external stents than in those comparing stents with no stents. One death occurred in the external-stent group (RR 0.33, 0.01 to 7.99; low-quality evidence). There were no cases of pancreatitis in participants who had internal stents compared with three in those who had external stents (RR 0.15, 0.01 to 2.73; low-quality evidence). The difference between internal and external stents on total hospital stay was uncertain due to the wide confidence intervals around the average effect of 1.7 days fewer with internal stents (9.18 days fewer to 5.84 days longer; 262 participants; 2 studies; low-quality evidence). The analysis of wound infection could not exclude a protective effect with either approach (RR 1.41, 0.44 to 4.48; 319 participants; 2 studies; moderate-quality evidence). Operative replacement of pancreatic juice versus not replacing pancreatic juice  There was insufficient evidence available from a small trial to ascertain the effect of replacing pancreatic juice. The investigators concluded that this systematic review has identified limited evidence on the effects of stents. They stated that they had not been able to identify convincing direct evidence of superiority of external over internal stents. They found a limited number of RCTs with small sample sizes. Further RCTs on the use of stents after pancreaticoduodenectomy are warranted.

Routine Nasogastric Decompression After Pancreaticoduodenectomy

Kunstman and associates (2013) stated that limited data exist for the use of naso-gastric decompression after PD, when post-operative nasogastric tube (NGT) use remains the standard of care.  These researchers examined the effects on patient outcomes of routine versus selective NGT use after PD.  A total of 250 patients undergoing PD between July 2003 and February 2012 by a single surgeon at an academic center were evaluated as 2 consecutive cohorts of 125 patients.  The first patient cohort had NGTs placed intra-operatively and maintained until clinically indicated.  In the second cohort, NGTs were selectively maintained only in rare circumstances, such as inability to extubate the patient post-operatively.  The primary outcomes evaluated were post-operative NGT insertion and re-insertion, delayed gastric emptying (DGE) incidence, time to dietary tolerance, and length of hospital stay (LOS).  Secondary analysis examined overall surgical morbidity and additional specific complications of interest.  Mean patient age was 63.4 years and the most common indication was pancreatic neoplasm.  Patients in both the routine and selective placement groups were evaluated in an intent-to-treat (ITT) manner.  In the selective group, NGTs were maintained in 9 patients post-operatively (7.2 %).  Need for NGT insertion and re-insertion and duration of NGT replacement did not differ significantly between selective and routine groups.  Overall complication rates were similar, however, patients in the selective group had decreased incidence of DGE (p = 0.015), LOS (p < 0.001), and time to dietary tolerance (p < 0.001).  The authors concluded that routine post-operative nasogastric decompression in patients undergoing PD appeared unnecessary in many cases, and could adversely impact post-operative course; however, selective NGT usage appeared an appropriate treatment strategy.

Park and co-workers (2016) stated that NGT placement after abdominal surgery has been a standard procedure for many decades.  In PD, DGE is still a leading post-operative complication, often resulting in patient anxiety or depression and prolonged hospital stays.  Such complications have led many surgeons to prefer post-operative naso-gastric decompression because of the greater risk of DGE.  These investigators examined the DGE and peri-operative outcomes after pylorus-preserving PD (PPPD) with or without routine gastrostomy.  From May 2009 to December 2014, a total of 228 patients underwent PPPD at the Department of Surgery, Gangnam Severance Hospital, Yonsei University.  The first cohort of 116 patients underwent surgery before June 2012 and uniformly underwent gastric decompression as a part of post-operative management.  The second cohort of 112 patients underwent operation after July 2012, and gastric decompression was selectively used to facilitate exposure during operation and was removed in the operating room at the end of surgery.  These researchers evaluated DGE incidence, time to dietary tolerance, LOS, and post-operative gastric tube re-insertion rates.  Gastric re-decompression was necessary in 38 patients (16.7 %), and there was a significant difference between the 2 groups (p = 0.006); 11 (9.8 %) patients in the no-tube gastrostomy group required NGT re-insertion, and 27 (23.3 %) in the routine gastrostomy group required that the gastrostomy tube be re-drainage.  There were no statistically significant differences in the frequency or severity of complications such as DGE or pancreatic leakage.  The authors concluded that the findings of this study showed that routine post-operative gastric decompression could be safely avoided in patients who undergo PPPD.

Gaignard and colleagues (2018) noted that since the spread of enhanced recovery programs, early withdrawal of the NGT is recommended after PD, although few data on the safety of this practice are available.  The se researchers examined the absence of nasogastric decompression after PD on post-operative outcome.  All consecutive patients undergoing PD between January 2014 and December 2015 at a single center were retrospectively analyzed.  Since May 2015, all operated patients had the NGT removed immediately after the procedure (NGT- group) and were compared to patients operated before this practice (NGT+ group), who had the NGT maintained until at least post-operative day 3.  During the study period, a total of 139 patients underwent PD, of whom 40 (29 %) were in the NGT- group and 99 (71 %) were in the NGT+ group.  The LOS and rate of post-operative complications of grade 2 or higher according to the Clavien-Dindo grading system were significantly higher in the NGT+ group [14 (11 to 25) versus 10 (8 to 14.2), p = 0.005; and 82.8 % versus 40 %, p < 0.001, respectively].  Incidence and severity of DGE grade B to C were also higher in the NGT+ group (45.5 % versus 7.5 %, p < 0.001).  There was no difference between the 2 groups concerning the 90-day post-operative mortality (p = 0.18).  The authors concluded that absence of systematic naso-gastric decompression after PD might reduce post-operative complications, DGE, and LOS.

Kleive and co-workers (2019) stated that evidence-based guidelines for enhanced recovery (ERAS) pathways after PD are available; and routine use of NGT after PD is not recommended.  In a prospective, observational study, these researchers examined the need for NGT reinsertion after PD performed within an ERAS setting.  This trial included patients undergoing PD in a tertiary referral hospital within the study period from 2015 throughout 2016.  Pre- and post-operative variables were collected . Patients requiring NGT re-insertion were identified.  Comparative analysis of patients with and without NGT re-insertion was carried out, as well as multi-variate analysis for risk factors for on-demand NGT re-insertion.  A total of 201 patients were included; 45 (22.4 %) patients required NGT re-insertion after PD.  A total of 32 (15.9 %) patients underwent a re-laparotomy.  Re-insertion of NGT in patients not undergoing a re-laparotomy occurred in 26 (15.4 %) patients.  The presence of a major post-operative complication was a risk factor for re-insertion of NGT, OR 5.27 (2.54 to 10.94, p = 0.001).  Patients with the need for a NGT re-insertion had a higher frequency of major post-operative complications and re-laparotomy compared to patients without the need of a NGT reinsertion, 26 (57.8 %) versus 32 (20.5 %), p < 0.001 and 19 (42.2 %) versus 13 (8.3 %), p < 0.001, respectively.  The authors concluded that the routine use of NGT after PD is not justified within an ERAS setting.  These researchers stated that immediate removal of the NGT after the procedure can be performed safely, and re-insertion on demand is rarely necessary in uncomplicated courses.

Bergeat and colleagues (2020) noted that although standardization of PD has improved post-operative outcomes, morbidity remains high.  Fast-track surgery programs appeared to improve morbidity; and avoiding NGT decompression (NGTD), already outdated in most major abdominal surgery, is strongly suggested after PD by fast-track surgery programs but lacks high-level evidence, especially regarding safety.  In a prospective, open-label, single-center, randomized clinical trial, these researchers examined if the absence of systematic NGTD following PD would reduce post-operative complications.  The IPOD study (Impact of the Absence of Nasogastric Decompression After Pancreaticoduodenectomy) was carried out at a high-volume pancreatic surgery university hospital in France.  A total of 155 patients who were 18 to 75 years of age and required PD for benign or malignant disease were screened for study eligibility.  Key exclusion criteria were previous gastric or esophageal surgery and severe co-morbidities.  Patients were randomly assigned (1:1) to systematic NGTD or to no NGTD and were followed-up until 90 days after surgery.  For patients without NGTD, the NGT was removed immediately after surgery, whereas for patients with NGTD, the NGT was removed 3 to 5 days after surgery.  The primary endpoint was the occurrence of post-operative complications grade II or higher using the Clavien-Dindo classification.  The primary endpoint and safety were evaluated in the ITT population.  From January 2016 to August 2018, a total of 125 screened patients were considered eligible for the study, and 111 were randomized to no NGTD (n = 52) or to NGTD (n = 59).  No patient was lost to follow-up.  The 2 groups had similar patient demographic and clinical characteristics at baseline.  The median (inter-quartile range [IQR]) age was 63.0 (57.0 to 66.5) years in the group with NGTD (38 [64.4 %] were men) and 64.0 (58.0 to 68.0) years in the group without NGTD (31 [59.6 %] were men).  The post-operative complication rates grade II or higher were similar between the 2 groups (RR, 0.99; 95 % CI: 0.66 to 1.47; p > 0.99).  Pulmonary complication rates (RR, 0.59; 95 % CI: 0.18 to 1.95; p = 0.44) and DGE rates (RR, 1.07; 95 % CI: 0.52 to 2.21; p > 0.99) were not significantly different between the 2 groups.  Median (IQR) length of hospital stay for patients without NGTD was not significantly different compared with those with NGTD (10.0 [9.0 to 16.3] versus 12.0 [10.0 to 16.0] days; p =0.14).  The authors concluded that the present study found no significant difference in post-operative complication occurrence of Clavien-Dindo classification grade II or higher between systematic NGTD and no NGTD after PD, suggesting that avoiding systematic naso-gastric decompression was safe for this indication.

Gao and associates (2020) stated that gastric decompression following pancreatic surgery has been a routine procedure for many years; however, this procedure has often been waived in non-pancreatic abdominal surgeries.  In a meta-analysis, these researchers examined the necessity of routine gastric decompression (RGD) following pancreatic surgery.  PubMed, the Cochrane Library, Embase, and Web of Science were systematically searched to identify relevant studies comparing outcomes of RGD and no gastric decompression (NGD) after pancreatic surgery.  The overall complications, major complications, mortality, DGE; clinically relevant DGE (CR-DGE), post-operative pancreatic fistula (POPF), clinically relevant POPF (CR-POPF), secondary gastric decompression, and the LOS were evaluated.  A total of 6 comparative studies with a total of 940 patients were included.  There were no differences between RGD and NGD groups in terms of the overall complications (OR = 1.73, 95 % CI: 0.60 to 5.00; p = 0.31), major complications (OR = 2.22, 95 % CI: 1.00 to 4.91; p = 0.05), incidence of secondary gastric decompression (OR = 1.19, 95 % CI: 0.60 to 2.02; p = 0.61), incidence of overall DGE (OR = 2.74; 95 % CI: 0.88 to 8.56; p = 0.08; I2 = 88 %), incidence of CR-POPF (OR = 1.28, 95 % CI: 0.76 to 2.15; p = 0.36), and incidence of POPF (OR = 1.31, 95 % CI: 0.81 to 2.14; p = 0.27).  However, RGD was associated with a higher incidence of CR-DGE (OR = 5.45; 95 % CI: 2.68 to 11.09; p < 0.001, I2 = 35 %), a higher rate of mortality (OR = 1.53; 95 % CI: 1.05 to 2.24; p = 0.03; I2 = 83 %), and a longer hospital LOS (WMD = 5.43, 95 % CI: 0.30 to 10.56; p = 0.04; I2 = 93 %).  The authors concluded that routine gastric decompression in patients following pancreatic surgery was not associated with a better recovery; and may be unnecessary after pancreatic surgery.

Antecolic Versus Retrocolic Reconstruction after Partial Pancreaticoduodenectomy

Huttner and colleagues (2022) noted that pancreatic cancer remains 1 of the 5 leading causes of cancer deaths in industrialized nations.  For adenocarcinomas in the head of the gland and pre-malignant lesions, partial pancreaticoduodenectomy represents the standard treatment for resectable tumors.  The gastro- or duodenojejunostomy after partial pancreaticoduodenectomy can be re-established via either an antecolic or retrocolic route.  The debate regarding the more favorable technique for bowel reconstruction is ongoing.  In a Cochrane review, these investigators compared the safety and effectiveness of antecolic and retrocolic gastro- or duodenojejunostomy after partial pancreaticoduodenectomy.  In this updated version, these researchers carried out a systematic literature search up to July 6, 2021 to identify all RCTs in the Cochrane Central Register of Controlled Trials (CENTRAL), the Cochrane Library 2021, Issue 6, Medline (1946 to July 6, 2021), and Embase (1974 to July 6, 2021).  They applied no language restrictions; and hand-searched reference lists of identified trials to identify further relevant trials; and searched the trial registries clinicaltrials.gov and World Health Organization International Clinical Trials Registry Platform for ongoing trials.  These investigators considered all RCTs comparing antecolic with retrocolic reconstruction of bowel continuity after partial pancreaticoduodenectomy for any given indication to be eligible.  The authors concluded that there was low- to moderate-certainty evidence suggesting that antecolic reconstruction after partial pancreaticoduodenectomy resulted in little to no difference in morbidity, mortality, LOS, or QOL.  Due to heterogeneity in definitions of the endpoints between trials, and differences in post-operative management, future research should be based on clearly defined endpoints and standardized peri-operative management, to potentially elucidate differences between these 2 procedures.  Novel strategies should be evaluated for prophylaxis and treatment of common complications, such as delayed gastric emptying.

Completion Pancreatectomy or a Pancreas-Preserving Procedure During Relaparotomy for Pancreatic Fistula After Pancreatoduodenectomy

Groen and colleagues (2021) stated that despite the fact that primary percutaneous catheter drainage has become standard practice, some patients with pancreatic fistula after pancreatoduodenectomy ultimately undergo a relaparotomy.  In a retrospective, cohort study, these researchers compared completion pancreatectomy with a pancreas-preserving procedure in patients undergoing relaparotomy for pancreatic fistula after pancreatoduodenectomy.  This trial entailed 9 institutions and included patients who underwent relaparotomy for pancreatic fistula after pancreatoduodenectomy from 2005 to 2018.  Furthermore, these investigators carried out a systematic review and meta-analysis according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.  From 4,877 patients undergoing pancreatoduodenectomy, 786 (16 %) developed a pancreatic fistula grade B/C and 162 (3 %) underwent a relaparotomy for pancreatic fistula.  Of these patients, 36 (22 %) underwent a completion pancreatectomy and 126 (78 %) a pancreas-preserving procedure.  Mortality was higher after completion pancreatectomy (20 (56 %) versus 40 patients (32 %); p = 0.009), which remained after adjusting for sex, age, body mass index (BMI), ASA score, previous re-intervention, and organ failure in the 24 hours before relaparotomy (adjusted OR 2.55, 95 % CI: 1.07 to 6.08).  The proportion of additional re-interventions was not different between groups (23 (64 %) versus 84 patients (67 %); p = 0.756).  The meta-analysis including 33 studies evaluating 745 patients, confirmed the association between completion pancreatectomy and mortality (Mantel-Haenszel random-effects model: OR 1.99, 95 % CI: 1.03 to 3.84).  The authors concluded that based on the current data, a pancreas-preserving procedure appeared preferable to completion pancreatectomy in patients in whom a relaparotomy is deemed necessary for pancreatic fistula after pancreatoduodenectomy.

Outcomes of Laparoscopic, Robotic, and Open Pancreatoduodenectomy

Weng and associates (2021) stated that robotic-assisted minimally invasive surgery is associated with worse oncologic outcomes for some but not other types of cancers.  In a propensity score-matched analysis, these researchers compared oncologic outcomes of robotic-assisted laparoscopic (RPD) versus open pancreatoduodenectomy (OPD) for pancreatic ductal adenocarcinoma (PDAC).  Treatment-naive PDAC patients undergoing either RPD or OPD at the authors’ hospital between January 2013 and December 2017 were included.  Propensity score matching was carried out at a ratio of 1:2.  The primary outcome was disease-free survival (DFS) and overall survival (OS).  A total of 672 cases were identified.  The propensity score-matched cohort included 105 patients receiving RPD and 210 patients receiving OPD.  The 2 groups did not differ in the number of retrieved lymph nodes [11 (7 to 16) versus 11 (6 to 17), p = 0.622] and R0 resection rate (88.6 % versus 89.0 %, p = 0.899).  There was no statistically significant difference in median DFS (14 [95 % CI: 11 to 22] versus 12 [95 % CI: 10 to 14] months (HR 0.94; 95 % CI: 0.87 to 1.50; log-rank p = 0.345) and median OS (27 [95 % CI: 22 to 35] versus 20 [95 % CI: 18 to 24] months (HR 0.77; 95 % CI: 0.57 to 1.04; log-rank p = 0.087) between the 2 groups.  Multi-variate COX analysis showed that RPD was not an independent predictor of DFS (HR 0.90; 95 % CI: 0.68 to 1.19, p = 0.456) or OS (HR 0.77; 95 % CI: 0.57 to 1.05, p = 0.094).  The authors concluded that comparable DFS and OS were observed between patients receiving RPD and OPD.  Moreover, these researchers stated that these preliminary findings need further confirmation with prospective RCTs.

In a network meta-analysis, Kabir and colleagues (2022) determined the optimal surgical approach for pancreatoduodenectomy by comparing outcomes after laparoscopic pancreatoduodenectomy (LPD), RPD and OPD.  These investigators carried out a systematic search of the PubMed, Embase, Scopus, and Web of Science databases to identify eligible RCTs and propensity-score matched studies.  A total of 4 RCTs and 23 propensity-score matched studies comprising a total of 4,945 patients were included for analysis.  Operation time for OPD was shorter than both LPD (MD -57.35, 95 % CI: 26.25 to 88.46 mins) and RPD (MD -91.08, 95 % CI: 48.61 to 133.56 mins), blood loss for RPD was significantly less than both LPD (MD -112.58, 95 % CI: 36.95 to 118.20 ml) and OPD (MD -209.87, 95 % CI: 140.39 to 279.36 ml), both RPD and LPD were associated with reduced rates of delayed gastric emptying compared with OPD (OR 0.59, 95 % CI: 0.39 to 0.90 and OR 0.69, 95 % CI: 0.50 to 0.95, respectively), RPD was associated with fewer wound infections compared with OPD (OR 0.35, 95 % CI: 0.18 to 0.71), and LPD patients enjoyed significantly shorter LOS compared with OPD (OR 0.43, 95 % CI: 0.28 to 0.95).  There were no differences in other outcomes.  The authors concluded that this network meta-analysis of high-quality studies suggested that when LPD and RPD were performed in high-volume centers, short-term peri-operative and oncologic outcomes were largely comparable, if not slightly improved, compared with traditional OPD.  Moreover, these researchers stated that these findings should be validated in further prospective, randomized studies.

Prophylactic Falciform Ligament Wrap Around the Hepatic Artery for the Prevention of Post-Pancreatectomy Hemorrhage

Welsch and colleagues (2021) noted that post-pancreatectomy hemorrhage (PPH) is a rare but potentially fatal complication following pancreatoduodenectomy.  Preventive strategies are lacking with scarce data for support.  In a multi-center RCT, these investigators examined if a prophylactic falciform ligament wrap around the hepatic and gastro-duodenal artery can prevent PPH from these vessels.  Subjects were patients who were scheduled for elective open partial pancreatoduodenectomy with pancreatojejunostomy between November 5, 2015 and April 2, 2020.  They were randomly allocated in a 1 : 1 ratio to undergo pancreatoduodenectomy with (intervention) or without (control) a falciform ligament wrap around the hepatic artery.  The primary endpoint was the rate of clinically relevant PPH from the hepatic artery or gastro-duodenal artery stump within 3 months following pancreatoduodenectomy.  Secondary endpoints were the rates of associated post-operative complications (e.g., post-operative pancreatic fistula (POPF) and PPH).  A total of 445 patients were randomized with 222 and 223 in each group.  Among the patients included in modified ITT analysis (207 in the intervention group and 210 in the control group), the primary endpoint was observed in 6 of 207 in the intervention group compared with 15 of 210 in the control group (2.9 % versus 7.1 %, respectively; OR of 0.39 (95 % CI: 0.15 to 1.02); p = 0.071).  Per protocol analysis showed a significant reduction in the intervention group (OR of 0.26 (95 % CI: 0.09 to 0.80); p = 0.017).  A soft pancreas texture (43 %) and the rate of a clinically relevant POPF were evenly (20 %) distributed between the groups.  The rate of any clinically relevant PPH including the primary endpoint and other bleeding sites was not significantly different between intervention and control groups (9.7 % versus 14.8 %, respectively).  The authors concluded that a falciform ligament wrap may reduce PPH from the hepatic artery or gastro-duodenal artery stump and should be considered during pancreatoduodenectomy.

Miscellaneous Indications for Pancreaticoduodenectomy

Schafer and colleagues (2002) examined the status of PD for pancreatic cancer and chronic pancreatitis (CP) using evidence-based methodology.  These researchers carried out a Medline search and manual cross-referencing to identify all relevant articles for classification and analysis according to their quality of evidence.  The search was limited to articles published between 1990 and 2001.  The mortality rate of PD has declined to less than 5 % for CP and 3 % to 8 % for pancreatic cancer.  In contrast, overall morbidity rates remained high, ranging between 20 % and 70 %.  Delayed gastric emptying represents almost half of all complications.  The overall 5-year survival rate for patients with pancreatic cancer remained poor, ranging between 5 % and 15 %, with a median survival of 13 to 17 months.  Mortality and morbidity were not related to the type of PD; however, patients with pancreatic cancer appeared to be at increased risk for complications.  Extended lymph node dissection and portal vein resection can be carried out with similar mortality and morbidity rates as standard procedures, but without apparent survival benefits in the long-term.  Major relief of pain was achieved in 70 % to 100 % of patients with CP.  The authors concluded that PD and its main modifications were safe and effective treatment modalities, especially in experienced centers with a high patient volume.  For CP, surgical resection provided major relief of pain; thus, increased QOL.  Overall survival for patients with pancreatic cancer was determined predominantly by the pathology within the resected specimen.

In a prospective, single-center study, Schniewind and co-workers (2006) examined QOL following classical partial PD (PPD) and pylorus-preserving PD (PPPD) in patients with adenocarcinoma of the pancreatic head, and also evaluated the influence of extended lymphadenectomy (ELA).  Between January 1993 and March 2004, QOL was analyzed in 91 patients; 34 underwent PPD and 57 had a PPPD; 70 patients had an ELA and 21 underwent regional lymphadenectomy (RLA).  QOL was evaluated using the European Organization for Research and Treatment of Cancer QLQ-C30 questionnaire and a pancreatic cancer-specific module.  Data were collected before operation and for 24 months following surgery.  The 5-year overall survival (OS) rate was 18 % for all patients and 21 % in those who had an R0 resection.  QOL was impaired for 3 to 6 months following surgery and then recovered to pre-operative levels.  There was no significant difference in long-term survival after PPD versus PPPD and ELA versus RLA.  Patients who had ELA reported clinically significant higher levels of diarrhea and pain.  PPPD showed a disadvantage in terms of pain.  The authors concluded that surgical techniques of resection and reconstruction did not affect QOL; however, extended lymphadenectomy was associated with an impairment in QOL.

Kempeneers and associates (2020) stated that CP is a complex inflammatory disease with pain as the predominant symptom.  Pain relief can be achieved using invasive interventions such as endoscopy and surgery.  This article was part of the international consensus guidelines on CP and presented the consensus guideline for surgery and timing of intervention in CP.  An international working group with 15 experts on CP surgery from the major pancreas societies (International Association of Pancreatology [IAP], American Pancreatic Association [APA], Japan Pancreas Society [JPS], and European Pancreatic Club [EPC]) evaluated 20 statements generated from evidence on 5 questions deemed to be the most clinically relevant in CP.  The GRADE approach was used to evaluate the level of evidence available for each statement.  To determine the level of agreement, the working group voted on the 20 statements for strength of agreement, using a 9-point Likert scale in order to calculate Cronbach's alpha reliability coefficient.

Strong consensus was obtained for the following statements:  

  • Surgery in CP is indicated as treatment of intractable pain and local complications of adjacent organs, and in case of suspicion of malignant (cystic) lesion.  
  • Early surgery is favored over surgery in a more advanced stage of disease to achieve optimal long-term pain relief.  
  • In patients with an enlarged pancreatic head, a combined drainage and resection procedure, such as the Frey, Beger, and Berne procedure, may be the treatment of choice. 
  • Pancreaticoduodenectomy is the most suitable surgical option for patients with groove pancreatitis.
  • The risk of pancreatic carcinoma in patients with CP was too low (2 % in 10 year) to recommend active screening or prophylactic surgery
  • Patients with hereditary CP had such a high risk of pancreatic cancer that prophylactic resection can be considered (lifetime risk of 40 % to 55 %).

Podda et al (2020) stated that although several non-randomized studies comparing robotic PD (RPD) and open PD(OPD) recently demonstrated that the 2 operative techniques could be equivalent in terms of safety outcomes and short-term oncologic efficacy, no definitive answer has arrived yet to the question as to whether robotic assistance could contribute to reducing the high rate of post-operative morbidity.  These researchers carried out a systematic literature search using Medline, the Cochrane Central Register of Controlled Trials, and Embase databases.  Prospective and retrospective studies comparing RPD and OPD as surgical treatment for peri-ampullary benign and malignant lesions were included in the systematic review and meta-analysis with no limits of language or year of publication.  A total of 18 non-randomized studies were included for quantitative synthesis with 13,639 patients allocated to RPD (n = 1,593) or OPD (n = 12,046).  RPD and OPD showed equivalent results in terms of mortality (3.3 % versus 2.8 %; p = 0.84), morbidity (64.4 % versus 68.1 %; p = 0.12), pancreatic fistula (17.9 % versus 15.9 %; p = 0.81), delayed gastric emptying (16.8 % versus 16.1 %; p = 0.98), hemorrhage (11 % versus 14.6 %; p = 0.43), and bile leak (5.1 % versus 3.5 %; p = 0.35).  Estimated intra-operative blood loss was significantly lower in the RPD group (352.1 ± 174.1 ml versus 588.4 ± 219.4 ml; p = 0.0003), whereas operative time was significantly longer for RPD compared to OPD (461.1 ± 84 mins versus 384.2 ± 73.8 mins; p = 0.0004).  RPD and OPD showed equivalent results in terms of retrieved lymph nodes (19.1 ± 9.9 versus 17.3 ± 9.9; p = 0.22) and positive margin status (13.3 % versus 16.1 %; p = 0.32).  The authors concluded that RPD was safe and feasible as surgical treatment for malignant or benign disease of the pancreatic head and the peri-ampullary region.  Equivalency in terms of surgical radicality including R0 curative resection and number of harvested lymph nodes between the 2 groups confirmed the reliability of RPD from an oncologic point of view.

Shyr et al (2021) PD (also known as "Whipple operation") is a time-consuming and technically demanding complex operation.  Traditionally, this procedure has been carried out most often by open approach, which results in a large and painful wound.  With the introduction of laparoscopic and robotic surgery, minimally invasive surgery (MIS) has emerged as a worldwide trend to improve wound cosmesis and to minimize wound pain.  Although MIS for PD has also been attempted at some centers, the role of MIS, either robotic or laparoscopic approach, has not been well-established for complex PD.  Given that laparoscopic PD has been limited by its technical complexity and the high level of advanced laparoscopic skills required for pancreatic reconstruction, a robotic surgical system is introduced to overcome several limitations related to the laparoscopic approach.  Providing high-quality three-dimensional (3D) vision, high optical magnification, articulation of robotic instruments, greater precision with suture targeting, and elimination of surgeon tremor, robotic surgical systems innovatively perform more delicate and complex procedures involving extensive dissection and suturing techniques such as PD.  Although associated with longer operative time, RPD has been claimed to have the benefits of less delayed gastric emptying, less blood loss, shorter length of post-operative stay, and lower wound infection rate, as compared with the traditional OPD.  Moreover, RPD appeared to be not only technically feasible but also justified without compromising the survival outcomes for pancreatic head and ampullary adenocarcinomas.  Th authors concluded that RPD could be recommended not only to surgeons but also to patients in terms of surgical feasibility, surgical outcomes, and patient satisfaction.

Furthermore, an UpToDate review on “Surgical resection of lesions of the head of the pancreas” (Reber, 2022) states that “The most common indication for resection of the head of the pancreas is the presence of a malignant or premalignant neoplasm of the pancreas or one of the other periampullary structures (bile duct, ampulla, or duodenum).  Certain types of neoplasms may be amenable to local excision (enucleation), and some benign conditions may also require pancreatic head resection (e.g., trauma, chronic pancreatitis).  Specific indications for pancreatic head resection include:

  • Pancreatic adenocarcinoma
  • Ampullary carcinoma
  • Ampullary adenoma
  • Neuroendocrine tumors
  • Cholangiocarcinoma
  • Duodenal neoplasm
  • Combined pancreatic/duodenal injury
  • Chronic pancreatitis

Outcomes of Laparoscopic, Robotic, and Open Pancreatoduodenectomy

Nieuwenhuijs et al (2020) stated that minimally invasive techniques have been suggested to achieve enhanced recovery and improved outcome after pancreaticoduodenectomy (PD).  These researchers described their experience and a stepwise technical implementation of the laparoscopic pancreaticoduodenectomy (LPD) during early introduction in 2016.  A team of 3 hepatopancreaticobiliary surgeons with extensive experience in open pancreaticoduodenectomy (OPD) and with advanced laparoscopic skills started a proctor-guided program with LPD.  The first 20 carefully selected cases were prospectively reviewed and compared with a matched OPD cohort.  In 20 months, 20 minimally invasive PDs were performed.  Reviewing the first 10 LPD cases, 7 patients (70 %) had anastomosis-related complications, versus 16 % in OPD (p = 0.001).  After consulting an international LPD expert, the team switched to a hybrid technique consisting of LPD followed by open reconstruction via midline mini-laparotomy (LPD-OR).  In the following 10 cases of LPD-OR; no anastomosis-related complications did occur (p = 0.342 OPD versus LPD-OR).  The authors concluded that safe introduction of new techniques in minimally invasive major abdominal surgery was imperative.  Based on this single-center experience, LPD-OR may be safer in the earliest phase of the learning curve of minimally invasive PD, as part of a stepwise implementation toward the fully laparoscopic technique.

Wang et al (2020) noted that LPD is a complicated procedure accompanied with high morbidity.  Hybrid LPD is usually used as an alternative/transitional approach.  In a retrospective study, these researchers examined if the hybrid procedure is a safe procedure during a surgeon's learning curve of LPD.  There were 48 hybrid LPD patients and 62 totally LPD (TLPD) patients selected from January 2016 to December 2018; their demographics, surgical outcomes, and oncological data were retrospectively collected.  Patient follow-up for the study continued until February 2020.  Patient demographics and baseline parameters were well balanced between the 2 groups.  Intra-operative conditions, overall operation time was shorter for TLPD compared to hybrid LPD (407.79 mins versus 453.29 mins, respectively; p = 0.035) and blood loss was less in TLPD patients compared to hybrid LPD patients (100.00 ml versus 300.00 ml, respectively; p < 0.001). There was no difference in transfusion rates between the 2 groups (hybrid LPD 16.7 % versus TLPD 4.8 %; p = 0.084).  Post-operative outcomes and intensive care unit (ICU) stay was longer in the hybrid LPD patient group (hybrid LPD 1-day versus TLPD 0-day, p = 0.002) and post-operative hospital stay was similar between the 2 groups (p = 0.503).  Re-operation rates, in-hospital, 30-day mortality, and 90-day mortality rates were comparable between the 2 groups (p =0.276, 1.000, 1.000, 0.884, respectively).  Surgical site infection, bile leak, Clavien-Dindo classification (CDC) of greater than or equal to 3, delayed gastric emptying, grade B/C post-operative pancreatic fistulae, and grade B/C post-pancreatectomy hemorrhage were not different between the 2 groups (p = 0.526, 0.463, 0.220, 0.089, 0.165, 0.757, respectively).  The tumor size, margin status, lymph nodes harvested, and metastasis were similar in the 2 groups (p = 0.767, 0.438, 0.414, 0.424, respectively).  Furthermore, the median overall survival (OS) rates were comparable between the 2 groups (hybrid LPD 29.0 months versus TLPD 30.0 months, p = 0.996) as were the progression-free survival (PFS) rates (hybrid LPD 11.0 months versus TLPD 12.0 months, p = 0.373).  The authors concluded that hybrid LPD was comparable to TLPD; hybrid LPD could be performed safely when some surgeons first started LPD (during the operative learning curve), while for skilled surgeons, TLPD could be applied initially.

The authors stated that this study had several drawbacks.  First, the number of cases involved was small; this was a relatively small sample size study.  Second, this was a retrospective, matched pair study.  Third, operations were not performed by the same surgeon, so there might exist a possible variation in the operative technique and peri-operative management of patients.

Wang et al (2021) noted that the benefit and safety of LPD for the treatment of pancreatic or periampullary tumors remain controversial.  Studies have shown that the learning curve plays an important role in LPD, yet there are no randomized studies on LPD after the surgeons have surmounted the learning curve.  In an open-label, multi-center RCT, these researchers compared the outcomes of OPD with those of LPD, when performed by experienced surgeons.  This trial was carried out in 14 Chinese medical centers; these investigators recruited patients aged 18 to 75 years with a benign, pre-malignant, or malignant indication for pancreatoduodenectomy.  Eligible patients were randomly assigned (1:1) to undergo either LPD or OPD.  Randomization was centralized via a computer-generated system that used a block size of 4.  The patients and surgeons were unmasked to study group, whereas the data collectors, outcome assessors, and data analysts were masked.  LPD and OPD were performed by experienced surgeons who had already performed at least 104 LPD operations.  The primary outcome was the post-operative length of stay (LOS).  The criteria for discharge were based on functional recovery, and analyses were carried out on a modified intention-to-treat (ITT) basis (i.e., including patients who had a pancreatoduodenectomy regardless of whether the operation was the one they were assigned to).  Between May 18, 2018, and December 19, 2019, these investigators assessed 762 patients for eligibility, of whom 656 were randomly assigned to either the LPD group (n = 328) or the OPD group (n = 328); 31 patients in each group were excluded and 80 patients crossed over (33 from LPD to OPD, 47 from OPD to LPD).  In the modified ITT analysis (297 patients in the LPD group and 297 patients in the OPD group), the post-operative LOS was significantly shorter for patients in the LPD group than for patients in the OPD group (median 15.0 days [95 % CI: 14.0 to 16.0] versus 16.0 days [15.0 to 17.0]; p = 0.02). 90-day mortality was similar in both groups (5 [2 %] of 297 patients in the LPD group versus 6 [2 %] of 297 in the OPD group, risk ratio [RR] 0.83 [95 % CI: 0.26 to 2.70]; p = 0.76).  The incidence rate of serious post-operative morbidities (Clavien-Dindo grade of at least 3) was not significantly different in the 2 groups (85 [29 %] of 297 patients in the LPD group versus 69 [23 %] of 297 patients in OPD group, RR 1.23 [95 % CI: 0.94 to 1.62]; p = 0.13).  The comprehensive complication index score was not significantly different between the 2 groups (median score of 8.7 [inter-quartile range [IQR] 0.0 to 26.2] versus 0.0 [0.0 to 20.9]; p = 0.06).  The authors concluded that in highly experienced hands, LPD was a safe and feasible procedure.  It was associated with a shorter LOS and similar short-term morbidity and mortality rates to OPD.  Nonetheless, the clinical benefit of LPD compared with OPD was marginal despite extensive procedural expertise.  These investigators stated that future research should focus on identifying the populations that will benefit from LPD.

Pan et al (2022) stated that pancreatic cancer is one of the deadliest cancers and PD is recommended as the optimal operation for resectable pancreatic head cancer.  Minimally invasive surgery, which initially emerged as hybrid-laparoscopy and recently developed into total laparoscopy surgery, has been widely used for various abdominal surgeries.  However, controversy persists regarding whether LPD is inferior to OPD for resectable pancreatic ductal adenocarcinoma (PDAC) treatment.  Further studies, especially randomized clinical trials, are needed to compare these 2 surgical techniques.  The TJDBPS07 Trial is designed as a prospective, randomized controlled, parallel-group, open-label, multi-center non-inferiority study.  All participating pancreatic surgical centers comprise specialists who have performed no less than 104 LPDs and OPDs, respectively.  A total of 200 strictly selected PD candidates diagnosed with PDAC will be randomized to receive LPD or OPD.  The primary outcome is the 5-year OS rate, whereas the secondary outcomes include OS, disease-free survival (DFS), 90-day mortality, complication rate, comprehensive complication index, LOS and intra-operative indicators.  These researchers hypothesize that LPD is not inferior to OPD for the treatment of resectable PDAC.  The enrolment schedule is estimated to be 2 years and follow-up for each patient will be 5 years.  The authors stated that this study received approval from the Tongji Hospital Ethics Committee of Tongji Medical College, Huazhong University of Science and Technology, and monitor from an independent 3rd-party organization.  Results of this trial will be presented in international meetings and published in a peer-reviewed journal.

In a meta-analysis, Yan et al (2023) compared the peri-operative outcomes of LPD to those of OPD for pancreatic and peri-ampullary tumors.  PubMed, Web of Science, Embase, and the Cochrane Library were searched to identify RCTs and non-randomized comparative trials (NRCTs) comparing LPD versus OPD for pancreatic and peri-ampullary tumors.  The main outcomes were mortality, morbidity, serious complications, and hospital LOS.  The secondary outcomes were operative time, blood loss, transfusion, POPF, PPH, bile leak (BL), DGE, lymph nodes harvested, R0 resection, re-operation, and re-admission.  RCTs were examined by the Cochrane risk-of-bias tool; and NRCTs were examined using a modified tool from the Methodological Index for Non-randomized Studies.  Data were pooled as OR or MD.  A total of 4 RCTs and 35 NRCTs concerning a total of 40,230 patients (4,262 LPD and 35,968 OPD) were included.  Meta-analyses showed no significant differences in mortality (OR 0.91, p = 0.35), serious complications (OR 0.97, p = 0.74), POPF (OR 0.93, p = 0.29), PPH (OR 1.10, p = 0.42), BL (OR 1.28, p = 0.22), harvested lymph nodes (MD 0.66, p = 0.09), re-operation (OR 1.10, p = 0.41), and re-admission (OR 0.95, p = 0.46) between LPD and OPD.  Operative time was significantly longer for LPD (MD 85.59 mins, p < 0.00001), whereas overall morbidity (OR 0.80, p < 0.00001), hospital LOS (MD -2.32 days, p < 0.00001), blood loss (MD -173.84 ml, p < 0.00001), transfusion (OR 0.62, p = 0.0002), and DGE (OR 0.78, p = 0.002) were reduced for LPD.  The R0 rate was higher for LPD (OR 1.25, p = 0.001).  The authors concluded that LPD was associated with non-inferior short-term surgical outcomes and oncologic adequacy compared to OPD when performed by experienced surgeons at large centers.  LPD may result in reduced overall morbidity, blood loss, transfusion, and DGE, but longer operative time.  Moreover, these researchers stated that further RCTs should address the potential advantages of LPD over OPD.

Qiu et al (2023) stated that the effectiveness of pancreaticoduodenectomy and OPD for pancreatic tumors is controversial.  In a systematic review and meta-analysis, these investigators compared the effectiveness of LPD and OPD in the treatment of pancreatic tumors.  PubMed, Embase, Cochrane Library and Web of science databases were searched for clinical studies on the treatment of pancreatic tumors with LPD and OPD.  The end time for the searches was July 20, 2022.  Rigorous inclusion and exclusion criteria were used to screen the articles, the Cochrane manual was used to examine the quality of the included articles, and the stata15.0 software was used for statistical analysis of the indicators.  A total of 16 studies were included, including 2 RCTs and 14 retrospective studies.  Involving a total of 4,416 patients, 1,275 patients were included in the LPD group and 3,141 patients in the OPD group.  The results of the meta-analysis showed that: the operation time of LPD was longer than that of OPD [WMD = 56.14, 95 % CI: 38.39 to 73.89), p = 0.001]; the amount of intra-operative blood loss of LPD was less than that of OPD [WMD = -120.82, 95 % CI: -169.33 to -72.30), p = 0.001].  No significant difference was observed between LPD and OPD regarding hospitalization time [WMD = -0.5, 95 % CI: -1.35 to 0.35), p = 0.250].  No significant difference was observed regarding post-operative complications [RR = 0.96, 95 % CI: 0.86 to 1.07, p = 0.463].  And there was no significant difference regarding 1-year OS and 3-year OS: 1-year OS [RR = 1.02, 95 % CI: 0.97 to 1.08), p = 0.417], 3-year OS [RR = 1.10, 95 % CI: 0.75 to 1.62), p = 0.614 %].  The authors concluded that in comparison with OPD, LPD resulted in less blood loss but longer operation time; thus, the bleeding rate per unit time of LPD was less than that of OPD.  LPD has obvious advantages.  With the increase of clinical application of LPD, the usage of LPD in patients with pancreatic cancer has very good prospect.  Moreover, these researchers stated that as a consequence of the limitations of this paper, in future studies, more attention should be paid to high-quality, multi-center RCTs.

Furthermore, an UpToDate review on “Overview of surgery in the treatment of exocrine pancreatic cancer and prognosis” (Fernandez-del Castillo and Jimenez, 2023) states that “Minimally invasive (laparoscopic, robotic-assisted) pancreaticoduodenectomy is technically feasible.  However, even with the available technology, minimally invasive pancreaticoduodenectomy is a complex operation that is only suited for selected patients.  Robotic-assisted pancreaticoduodenectomy has not reduced rates of perioperative morbidity (e.g., pancreatic fistula) or mortality”.  Laparoscopic pancreaticoduodenectomy is not listed in the “Summary and Recommendations” section of this UTD review.

Regional Vessels Wrapping Following Pancreaticoduodenectomy for Reduction of the Risk of Post-Operative Extra-Luminal Bleeding

Nour et al (2022) stated that post-pancreatectomy bleeding is a potentially fatal complication that resulted from the erosion of the regional visceral arteries, mainly the hepatic artery and stump of the gastro-duodenal artery, caused by a leak or fistula from the pancreatic anastomosis.  In a systematic review, these investigators examined if wrapping of regional vessels with omentum or falciform/teres ligament following pancreaticoduodenectomy would reduce the risk of extra-luminal bleeding.  Standard medical electronic databases were searched with the help of a local librarian and relevant published RCTs and any type of comparative study were short-listed according to the inclusion criteria.  The summated outcome of post-operative extra-luminal bleeding in patients undergoing pancreaticoduodenectomy was examined using the principles of meta-analysis on RevMan 5 statistical software.  A total of 2 RCTs and 5 retrospective studies on 4,100 patients undergoing pancreaticoduodenectomy were found suitable for this meta-analysis.  There were 1,404 patients in the wrapping-group (WG) and 2,696 patients in the no-wrapping group (NWG).  In the random effects model analysis, the incidence of extra-luminal hemorrhage was statistically lower in WG (OR 0.51, 95 % CI: 0.31 to 0.85, Z = 2.59, p = 0.01).  There was moderate heterogeneity between the studies; however, it was not statistically significant.  The authors concluded that wrapping of regional vessels (using omentum, falciform ligament or ligamentum teres) following pancreaticoduodenectomy appeared to reduce the risk of post-operative extra-luminal bleeding.  However, more RCTs of robust quality recruiting a greater number of patients as well as comparing different types of wrapping material are needed to validate these findings as this study presented the combined data of 2 RCTs and 5 retrospective studies.

The authors stated that the main drawback of this study was that it was a combined analysis of RCTs and retrospective studies, which was a potential source of biased evidence.  The included RCTs were of reasonable quality but the retrospective comparative studies did not score well according to the criteria of quality assessment.  A larger, multi-center RCT is needed to confirm these findings before the standard recommendation of wrapping of the regional vessels following pancreaticoduodenectomy.


References

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