Modified reconstruction approach after pancreaticoduodenectomy optimizes postoperative outcomes: Results from a multivariate cohort analysis
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- Published online on: July 26, 2024 https://doi.org/10.3892/etm.2024.12666
- Article Number: 377
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Copyright: © Parasyris et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Periampullary carcinomas include neoplasms that originate from the epithelium of the pancreas, the ampulla of Vater, the distal bile duct and the duodenum, which results in the following four types of adenocarcinomas: Pancreatic ductal adenocarcinoma (PDAC), which is the most common, followed by ampullary adenocarcinoma (AA), distal cholangiocarcinoma (DCC) and duodenal adenocarcinoma (DA) (1). PDAC represents 17% of all new cancer cases in the digestive tract, with 60,430 estimated new cases in 2021 in the USA (2,3). In the United States, median overall survival (OS) differs among these adenocarcinomas, with DA having the most favorable prognosis (54-86 months), followed by AA (38-49 months) and DCC (18-33 months), whereas PDAC has the worst prognosis, given that its OS is only 11-18 months (4). Besides periampullary carcinoma, another lesion that can be considered benign but is a precursor of pancreatic adenocarcinoma is intraductal papillary mucinous neoplasm (IPMN). IPMNs are mucous-producing, cystic tumors originating from the pancreatic epithelium of the main pancreatic duct or its side branches (5).
Regardless of tumor histology, the surgical treatment of periampullary neoplasms includes pancreaticoduodenectomy (PD) or Whipple's procedure, lymph node resection, as well as vascular reconstruction if necessary (6). PD is associated with increased rates of morbidity and major postoperative complications, such as delayed gastric emptying (DGE), which is the most common complication, pancreatic leak or fistula, postoperative hemorrhage requiring reoperation, embolism or blood transfusion, bile leak and intra-abdominal abscess (7). Over the last few years, the technique has significantly improved and it is now considered a safer procedure with a hospital mortality rate of <5% in high-volume centers (8). The aim of the present cohort study was to compare modified PD (mPD) with standard PD (StPD), in terms of postoperative complications, especially pancreatic fistula, which is the most severe adverse event. Furthermore, several perioperative factors for both groups of patients were assessed, concerning morbidity, mortality and OS.
Materials and methods
Study design
A retrospective cohort study was conducted at the Surgical Departments of the Attikon University Hospital (Athens, Greece) between January 2010 and December 2019. The present study received ethics approval by the Hospital's Scientific and Bioethics Committee (approval no. 47929/16-12-16).
Eligibility criteria
All consecutive patients undergoing PD for resectable pancreatic cancer or periampullary neoplasms at the Attikon University Hospital within the duration of the study period were recorded. Pancreatic cancer was defined as resectable in the case of absence of distant metastases, and absence of local tumor extension to the celiac axis, the hepatic artery and the superior mesenteric vasculature. Patients who were deemed as borderline-resectable received neoadjuvant cytotoxic chemotherapy, and were then restaged and reevaluated for resection.
The patients were assigned into two groups, according to the type of PD that they underwent. The type of modification after PD was selected by the lead surgeon based on their experience and the characteristics of the patient. In the first cohort, the patients underwent a mPD, while the patients in the second cohort underwent the StPD. The collected variables included patient demographics, presentation of jaundice, past medical history, tumor markers, intraoperative and anesthesiologic parameters, hospitalization days, postoperative complications, pathology, indication and cause of reoperation, 30-day-survival, postoperative mortality and OS. Pathological staging of malignant tumors was performed according to the Eighth Edition of the Cancer Staging Manual edited by the American Joint Committee on Cancer (9).
Pre-operative work-up
Pre-operative work-up for all patients included a routine computed tomography scan to assess the characteristics and size of the lesion. Abdominal magnetic resonance imaging, endo-ultrasonography and magnetic resonance cholangiopancreatography were also performed for selected patients. Biliary drainage before surgery was achieved with endoscopic retrograde cholangiopancreatography if the serum bilirubin was >15 mg/dl or if the patient presented with acute cholangitis (10).
Intraoperative parameters
Mannitol was used by some anesthesiologists to prevent postoperative renal dysfunction in patients with obstructive jaundice, based on a previous study (11).
Surgical technique
Two different surgical techniques were performed with an open approach. All of the patients in the first cohort underwent a mPD procedure with an isolated pancreaticojejunostomy and pylorus preservation, whereas all of the patients in the second cohort underwent the StPD procedure without pylorus preservation. The mPD used a Roux-en-Y configuration, draining the pancreatic duct and the stomach via the short limb and the bile duct separately via a long jejunal limb. The pylorus was preserved and mechanically dilated with two fingers prior to the construction of the gastrojejunostomy (12), retaining propulsion, while its dilatation removes an obstacle from gastric emptying. For StPD, the configuration was performed with all three anastomoses in a single jejunal loop. In all cases of mPD and StPD, the pancreatojejunostomy was performed duct to mucosa with interrupted, absorbable polydioxanone sutures, reinforced with a second continuous prolene layer incorporating seromuscular jejunum, pancreatic parenchyma and serosa. In both techniques, a stent was used in the pancreatojejunostomy.
Postoperative outcomes
The primary outcome assessed in the present study was perioperative mortality, defined as death within 30 days after operation or within index admission, irrespective of cause.
As secondary outcomes, overall morbidity, hospitalization time, recurrence and OS were recorded. Complications were categorized according to the Clavien-Dindo classification (13). Causes of morbidity were postoperative pancreatic fistula (POPF) or anastomotic leak from the pancreaticojejunostomy, DGE, postoperative hemorrhage necessitating blood transfusion, embolization or relaparotomy, intra-abdominal abscess, and postoperative hepaticojejunostomy leak. POPF, in particular, was defined as ‘drain output of any measurable volume of fluid on or after postoperative day 3 with an amylase content greater than 3 times the serum amylase activity, associated with a clinically relevant development/condition related directly to the postoperative pancreatic fistula’. A grading system was also used for POPF, in which a grade A POPF was now redefined and called a ‘biochemical leak’, because it has no clinical importance and no longer refers to a true pancreatic fistula, a grade B POPF referred to patients requiring medical or minimally invasive treatment, and a grade C POPF was a leakage in need of surgical intervention (12,14). Patients were assessed as to whether or not they received neoadjuvant or adjuvant chemotherapy. OS was determined from the date of operation until the date of death from any cause or the final date of follow-up, which was at the end of December 2021.
Statistical analysis
Sample characteristics were summarized as absolute (n) and relative (%) frequencies (categorical variables), or as the median and interquartile range (continuous variables). P-values were determined using the Fisher's exact test for categorical variables, and non-parametric tests (Mann-Whitney U-test) for continuous variables.
Analysis of overall mortality was based on survival methods. Univariate tests of association with potential predictors were performed using the log-rank test for categorical variables and univariate Cox models for continuous variables (data not shown). Multivariate models were based on proportional-hazards Cox regression. Hazard ratios >1 indicated higher probabilities of death, whereas hazard ratios <1 indicated lower probabilities of death. Survival probabilities over time were graphically presented using the Kaplan-Meier method and were analyzed using the log-rank test.
Analysis of time to hospital discharge and time to recurrence were also based on time-to-event analyses; however, in these two cases, methods for competing risks were used considering that death can in both cases occur before the main event of interest (i.e. hospital discharge or recurrence). Univariate tests were based on respective Fine and Gray models of the cumulative incidence function (data not shown). The same models were used for multivariate analysis. Subdistribution hazard ratios >1 indicated higher probabilities of a positive outcome (i.e. hospital discharge or recurrence), whereas subdistribution hazard ratios <1 indicated lower probabilities of a positive outcome.
In all multivariate models, the type of operation, sex and age variables were kept in the models irrespectively of their statistical significance due to interest in them or their potential confounding effects.
For binary outcomes, associations of the outcomes with potential prognostic factors were assessed using multivariate logistic regression. In all cases, odds ratios >1 indicated higher probabilities of a positive outcome (i.e. presence of the outcome), whereas odds ratios <1 indicated lower probabilities of a positive outcome. P<0.05 was considered to indicate a statistically significant difference. All analyses were performed using Stata version 15.1 (StataCorp, LLC).
Results
Patient characteristics
Between January 2010 and December 2019, PD was performed in 218 patients. Among them, 123 patients underwent a mPD procedure, while 95 underwent the StPD procedure. The median age was 67 years, ranging from 25 to 89 years. A total of 117 patients were male and 101 patients were female. The patients' demographics and comorbidities are presented in Table I. There were no differences between the two groups in terms of sex (male 54.5% vs. 52.6%; P=0.891), smoking status (P=0.338), body mass index (BMI) status (25.10 vs. 25.87 kg/m2; P=0.349) or American Society of Anesthesiology (ASA) scores (P=0.204) (15). Moreover, there were no major differences in the incidence of comorbidities or past surgical history.
Preoperative factors
The incidence rate of jaundice was higher among patients who underwent StPD compared with that in patients who underwent mPD (64.2% vs. 78.9%; P=0.024). However, no differences were noted in terms of blood biomarkers, such as neutrophil-to-lymphocyte ratio (NLR; 2.57 vs. 2.83; P=0.554), CEA (3.20 ng/ml vs. 2.70 ng/ml; P=0.118) and CA19-9 (58.40 U/ml vs. 50.95 U/ml; P=0.365) (Table I).
Pathology
The vast majority of neoplasms were adenocarcinomas of the pancreas in both groups (62.6% vs. 60%) followed by adenocarcinoma of Vater (12.2% vs. 12.6%), bile duct adenocarcinoma (7.3 vs. 13.7%) and IPMN (5.7% vs. 6.3%). In total, benign neoplasm or premalignant entities represented 9.8% of the tumors in the first group and 9.5% of neoplasms in the second group. There were no significant differences between the two groups regarding the tumor size (3.0 cm vs. 2.8 cm; P=0.369) (Table I).
Intraoperative parameters
Table I also shows intraoperative outcomes and anesthesiologic data for the two study groups. No differences were noted in the type of analgesia that was used during the operation, except for the use of PCA morphine and tramadol, which was higher in the first group (9.6 vs. 1.1%; P=0.006). The operative time was significantly lower in the first group (190 min vs. 320 min; P<0.001) as were the units of blood transfused [red blood cell (RBC) units (P=0.002) and fresh frozen plasma (FFP) units (P<0.001)].
Postoperative outcomes. Primary outcome
Table II shows that the perioperative mortality rates (4.1% vs. 14.7%; P=0.007) were significantly higher in the second group compared with those in the first group. Multivariate analysis for the probability of perioperative mortality revealed that StPD (P=0.040), history of coronary disease (P=0.037), intraoperative use of mannitol (P=0.009) and increased transfusion with RBCs (P=0.032) were independent significant risk factors associated with an increased rate of perioperative mortality (Table III).
 | Table IIIMultivariate logistic regression (without any postoperative factor) model for the probability of perioperative mortality and death. |
Secondary outcomes. Significant differences were also reported in terms of hospitalization stay, postoperative complications and morbidity. Patients in the first group had a shorter hospitalization stay compared with that in patients in the second group (11 days vs. 20 days; P<0.001). Moreover, the rates of POPF (4.9% vs. 28.4%; P<0.001) and the grades of POPF (Grade B: 1.6% vs. 16.8%; Grade C: 3.3% vs. 11.6%; P<0.001), DGE (7.3% vs. 42.1%; P<0.001) and postoperative hemorrhage (3.3% vs. 20%; P<0.001), as well as reoperation (6.5% vs. 15.8%; P=0.043), intensive care unit (ICU) admission (8.1% vs. 18.9%; P=0.024) and overall morbidity (Clavien-Dindo grades III-V: 14.7% vs. 42%; P<0.001), were lower in the mPD group than in the StPD group. However, no differences were noted regarding the rates of postoperative abscess (3.3% vs. 9.5%; P=0.081), the overall recurrence (41.5% vs. 38.9%; P=0.385) and the death rate (51.2% vs. 53.7%; P=0.678) or the median survival (35 months vs. 30 months; P=0.247) between the groups. The median follow-up was 25 months for the mPD group and 16.5 months for the StPD group (P=0.082) (Table II).
Hospitalization days. Multivariate analysis showed that StPD (P<0.001), history of coronary disease (P<0.001), increased BMI (P=0.002), biochemical leak (P<0.001), grade C POPF (P=0.001), DGE (P<0.001) and reoperation (P=0.001) were independent significant risk factors associated with longer hospital stay. On the other hand, the use of patient-controlled analgesia morphine and tramadol as analgesia (P<0.001) seemed to act as a protective factor for shorter hospitalization stay (Table IV). Fig. 1 depicts the cumulative probabilities of discharge by time since operation with death as competing risk.
POPF. Multivariate analysis for the probability of clinically significant POPF revealed that StPD (P<0.001), increased NLR (P=0.012), history of previous abdominal surgery (P=0.049) and AA histological type (P=0.014) were independent significant risk factors associated with an increased rate of clinically significant POPF (Grade B and C) (Table V).
| Table VMultivariate logistic regression model for the probability of clinically significant postoperative pancreatic fistula, delayed gastric emptying and hemorrhage. |
DGE. Multivariate analysis for the probability of postoperative DGE showed that StPD (P<0.001), clinically significant POPF (P=0.001) and reoperation (P=0.004) were independent significant risk factors associated with an increased rate of DGE in the patients (Table V).
Hemorrhage. Multivariate analysis for the probability of postoperative hemorrhage necessitating blood transfusion, embolization or relaparotomy showed that only clinically significant POPF (P=0.001) and increased intraoperative transfusion of FFP (P=0.019) were independent significant risk factors associated with an increased rate of postoperative hemorrhage (Table V).
Reoperation. The multivariate logistic regression model for the probability of reoperation revealed that presentation of jaundice (P=0.045), clinically significant POPF (P=0.001) and postoperative hemorrhage (P<0.001) were independent significant risk factors associated with an increased rate of reoperation, whereas history of past abdominal surgery may act as a protective factor regarding the need for reoperation (P=0.009) (Table VI).
| Table VIMultivariate logistic regression model for the probability of reoperation and ICU admission. |
ICU admission. Multivariate analysis for the probability of ICU admission showed that history of coronary disease (P=0.013), presentation of jaundice (P=0.026), DGE (P=0.012) and reoperation (P<0.001) were independent significant risk factors associated with an increased rate of ICU admission (Table VI).
Recurrence. Fig. 2 depicts the cumulative probabilities of recurrence by time since operation, with death as a competing risk. There was no significant difference regarding the recurrence rates between the two groups (P=0.353). Multivariate analysis for the probability of recurrence showed that higher pathological stage of malignant tumors (stage II/IIA: P=0.073, stage IIB: P=0.026, stage III: P=0.016) were independent significant risk factors associated with increased rate of recurrence (Table VII).
OS. The 1-, 2- and 5-year survival rates were 79.4, 61.5 and 37.9% for the patients operated with mPD, and 67.3, 56.2 and 37.8% for the patients operated with StPD (Fig. 3). Fig. 4 depicts the OS rates according to the histological type of the neoplasms, with a 5-year survival rate of 22.8% for the PDAC, 56.7% for AA and 27.4% for DCC. Multivariate analysis for the probability of death revealed that StPD (P=0.032), II and III ASA score (P=0.041 and P=0.001, respectively), and jaundice presentation (P=0.034) were independent significant risk factors associated with increased rate of death (Table III).
Discussion
In 1945, Allen O. Whipple reported for the first time a one-stage procedure for the removal of periampullary neoplasms with a postoperative mortality rate of 31% (12). Since then, >70 years of experience in the PD procedure have resulted in a decrease in hospital mortality to <5% in high-volume centers (8).
Notably, an increased rate of intraoperative mortality when using mannitol was determined in the present study, resulting in omission of the diuretic from the anesthesiologists' practice. The reason for this association has yet to be determined and may be assessed in future studies.
The global morbidity rates of PD remain high, ranging between 32 and 52%, and the majority of complications result from POPF, with an incidence rate of 10-28.5%, and DGE, with an incidence rate of 20-40% (8,14-20). One of the most useful tools to depict morbidity is the Clavien-Dindo classification. In the present study, severe postoperative complications (Clavien-Dindo grades III-V) were detected in only 14.7% of patients in the mPD group, whereas in the StPD group, overall morbidity remained relevantly high at 42.0%.
Pancreatic fistulas remain an important complication of the Whipple procedure and significantly contribute to overall morbidity after a PD. The risk factors for POPF include soft texture of the parenchyma, a small pancreatic duct, the presence of activated digestive fluids, decreased regional blood supply, the surgeon's experience and the underlying disease pathology. Several surgeons have assessed different approaches to eliminate POPF and its serious complications. Nonetheless, currently, there is no specific technique that can substantially eradicate the development of POPF (21). The aim of the current study was to assess a number of preoperative and intraoperative factors, and to determine how they alter the postoperative course after a PD. Among these perioperative factors, the type of the procedure performed was revealed to be associated with significantly lower morbidity (14.7% vs. 42.0%; P<0.001) and perioperative mortality rates (4.1% vs. 14.7%; P=0.007). Besides the StPD, the present study introduced a new technique regarding the restoration of gastrointestinal continuity, which involves a Roux-en-Y configuration, with the pancreaticojejunostomy and gastrojejunostomy in the short limb and the hepaticojejunostomy separately in the long jejunal limb. Pancreatic leak is the main risk of StPD, whereas optimization of the type of anastomosis could reduce the risk of the leaks. The theory behind this approach is that the activation of pancreatic enzymes (lipase, protease, amylase) by bile salt and alkalized pH could possibly be avoided when the pancreatic anastomosis is placed far from the biliary tree and closer to the low pH of the gastric fluid. This may be due to the fact that the activity of pancreatic amylase and lipase is dependent on the pH, and thus is decreased when placed away from the hepaticojejunostomy (12). The present results showed that, overall, clinically significant POPF complicated 15.1% of the cases. Nonetheless, the rates were different between the two groups. Only 4.9% of patients operated with the mPD procedure were complicated with POPF, whereas in the StPD group the POPF rate was 28.4%. In addition, in the multivariate analysis, the type of PD performed was indicated as an independent risk factor for the probability of POPF.
Lee et al (17) suggested that pylorus preservation is an independent risk factor for DGE; their results showed that there was a significant difference in the DGE rates between patients that underwent pylorus-preserving and pylorus-resected PD (39.2% vs. 8.8%; P<0.001) (17). In the mPD procedure described in the present study, the pylorus was preserved. Nonetheless, a key step of the suggested procedure is the additional mechanical dilation of the pyloric muscle fibers prior to the construction of the anastomosis. This allows for future preservation of the propulsion of the pylorus, while removing the obstacle of a constricted muscle during the initial postoperative days. In addition, nonactivation of pancreatic proenzymes (trypsinogen, chymotrypsinogen, procarboxypeptidase) close to the pancreaticojejunal anastomoses could be associated with reduced local inflammation and gastroparesis, while placement of the hepaticojejunostomy distally from the stomach prevents bile salt reflux (11). This could explain the extremely low DGE rates that were recorded in the mPD group when compared not only to the StPD group (7.3 vs. 42.1%), but also to all common rates reported in the literature (7,13-19).
On a long-term basis, the most significant aspect of a novel surgical technique is the ability to prolong the life duration of a patient. The global mortality rate associated with PD has steadily decreased in experienced centers to 5% (8,14-20). Arjunan et al (15) observed that there was not a notably significant survival difference between patients with POPF and those without POPF (P=0.457). Veillette et al (22) demonstrated that there was a statistically significant increase in mortality in the presence of a fistula (P<0.01), with an ~8-fold increase detected (9.3% of patients with fistula and 1.2% in the group without fistula). In a previous study, it was revealed that the major means by which a fistula can lead to death is hemorrhage (22). Thus, we can easily conclude that the presence of a POPF is a major determinant of morbidity but not mortality. As concerns the histological type, PDAC has been reported to have the worst prognosis (6). Cameron and He (8) showed that the 5-year survival rate for PDAC was 19% in the first 1,000 PDs and 24% in the second 1,000 (P=0.02). The difference between these two groups may demonstrate an increase in margin-negative resections and improved adjuvant therapy, but there was no statistically significant difference. These results were similar to the present outcomes, with a 5-year survival rate of 22.8% for PDAC. In the two study groups, there was a statistically significant difference in the perioperative mortality (4.1 vs. 14.7%; P=0.007) but not in the 5-year survival rate (51.2% vs. 53.7%; P=0.678). Therefore, even if the perioperative mortality and morbidity were radically diminished in the mPD group, the overall long-term outcome after both procedures was similar. Nonetheless, multivariate analysis for the probability of death revealed that StPD (P=0.032) was an independent significant risk factor associated with an increased rate of death. On the other hand, IPMN histopathology (P=0.007) seemed to act as a protecting factor against the incidence of death. Further studies are required to conclude if the modified technique used in the present study can increase the OS of patients.
The present study has some limitations. First, it has a moderate sample size and a retrospective study design. Although it is a single institutional study, surgical procedures were carried out by four different surgical teams, which may be a source of bias. However, they have almost an equal experience in PD. The present study emphasizes the importance of adhering to a single reproducible anastomotic technique in lowering morbidity and the survival data adds to the literature regarding cancer care.
In conclusion, the present study demonstrated that the proposed configuration for PD was associated with better postoperative outcomes. It is hypothesized that this technique creates a biochemical balance. This balance, and not surgical dexterity, may diminish inflammation and enhance the healing process, leading to better outcomes. The literature lacks evidence regarding the Roux-en-Y technique of gut reconstruction in the PD procedure and its contribution to POPF-related morbidity and mortality. Given the retrospective nature of this research, a randomized prospective study from other pancreatic centers is necessary to validate the results.
Acknowledgements
Portions of the present study were presented as a poster during the Congress of the American College of Surgeons, and the abstract was published in the Journal of the American College of Surgeons (https://journals.lww.com/journalacs/citation/2021/11002/could_a_modified_reconstruction_approach_after.289.aspx).
Funding
Funding: No funding was received.
Availability of data and materials
The data generated in the present study may be requested from the corresponding author.
Authors' contributions
NA, VS, PV, PM, PP and SP substantially contributed to the conception and design of the study. VN, SAM and SP contributed to the acquisition and interpretation of the data, as well as manuscript drafting. TS contributed to study design, and manuscript drafting and revision. NP contributed to the statistical analysis of the manuscript and interpretation of the data. NA, VS and VP revised the final manuscript. All authors read and approved the final manuscript, and agreed to be accountable for all aspects of the work, so that any questions relating to research integrity or scientific accuracy in any part of the study are appropriately investigated and resolved. SP and VN confirm the authenticity of all the raw data.
Ethics approval and consent to participate
The present study received ethics approval from the Scientific and Bioethics Committee of Attikon University Hospital (approval number: 47929/16-12-16; Athens, Greece). Consent to participate was deemed unnecessary due to the retrospective nature of the study.
Patient consent for publication
Written informed consent for publication was retrospectively obtained from all patients of the study. In the case of deceased patients, informed consent was obtained from close relatives.
Competing interests
The authors declare that they have no competing interests.
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