Investigating the differences in patients with pancreatic ductal adenocarcinoma who
receive either a classic
pancreatoduodenectomy versus a pylorus- preserving pancreatoduodenectomy
Rahul Rihel
Supervisors: Ivar Prydz Gladhaug, Dyre Kleive
Project Thesis
FACULTY OF MEDICINE UNIVERSITY OF OSLO
January 2021
Abstract:
Background: Radical resection of tumours of the head of the pancreas is achieved through two different operative methods, pancreatoduodenectomy (PD) and pylorus-preserving pancreatoduodenectomy (PPPD). Metanalyses have shown that PD is not superior to PPPD in terms of peri and post-operative outcome. The aim of this paper is to investigate if there are any potential differences in patients that receive either a PD or a PPPD in the population that is examined. These differences include preoperative demographics, perioperative data, post-operative complications, long-term survival, and in particular any differences in
resection margin between the two forms of surgery.
Method: Between January 2016 and December 2017 at OUS, Rikshospitalet, after applying certain exclusion criteria, 75 total patients were included, of which 32 patients received a PD operation, and 43 patients received a PPPD operation. Data was collected from a
prospectively maintained database.
Results: At follow up, 17 of the total 75 patients were alive, 11 from the PD population and 6 from the PPPD population. There were no differences between the PD and PPPD populations with regards to demographic characteristics, post-operative complications, morbidity, and survival. In the PD population, there were significantly more positive SMA and SMV resection margins, in addition to a significantly higher number of margins involved in the PD
population. Multivariate analysis showed that positive SMA and SMV resection margins had no impact on survival.
Conclusion: There were no particular differences in outcome, both short-term and long- term, for the patients receiving either a PD or PPPD. Significantly more positive SMA and SMV resection margins were observed in the PD population, however, the significance of this finding is unclear and should be investigated further.
Table of Contents
Introduction: ... 4
Background information: ... 4
Objective: ... 5
Method: ... 5
Surgical technique: ... 6
Definitions: ... 8
Pathological assessment: ... 10
Statistical methods: ... 10
Results: ... 11
Discussion: ... 24
Further investigation and limitations: ... 31
Conclusion: ... 32
Bibliography: ... 33
Introduction:
Background information:
Radical tumour resection is the only treatment modality that is curative for patients who suffer from pancreatic cancer. Only 10-15% of patients with pancreatic cancer are eligible to receive surgical treatment.1 Pancreatic ductal adenocarcinomas (PDAC) is the tumour form that is the most common in the pancreas, and it is a disease that has one of the highest mortality rates, with a five-year survival rate of approximately about 7.2% in some population studies.2 This poor survival rate is mainly due to the tendency of PDAC’s to rapidly form metastases, in addition to its resistance to treatment modalities such as radiation and chemotherapy.1
There are two surgical procedures that will be discussed in this paper that are used to treat PDAC, where one of them is pancreatoduodenectomy (PD). This form of surgery was described in a paper published by Allen O. Whipple in 1935.3 Briefly described, in PD there is en bloc resection of the pancreatic head, the duodenum, the distal common bile duct, gallbladder, and distal stomach. Adjacent lymph nodes are also removed. This is then followed by a reconstruction of the gastrointestinal tract, including a duodenojejunostomy, hepaticojejunostomy, and pancreatojejunostomy.4
Another surgical method that is used in treating PDAC, is pylorus-preserving
pancreatoduodenectomy (PPPD), which was popularised by Traverso and Longmire in 1978.5 This form of surgery is similar to the aforementioned PD, however this form of surgery preserves the pylorus and first portion of the duodenum.6
Other surgical methods such as total pancreatectomy and distal pancreatectomy will not be covered in this paper, as this paper focuses primarily on PDAC located in the head and neck of the pancreas which is commonly resected through either PD or PPPD.
The discussion concerning the comparison between PD and PPPD is intriguing as there does not appear to be a common consensus as to which form of surgery is to be favoured. A recent meta-analysis from 2019 indicated that PD was comparable to PPPD in terms of multiple relevant parameters, including postoperative pancreatic fistulas,
perioperative blood loss, duration of surgery, length of hospital stay, and mortality.4 One parameter that is often brought up in this discussion between PPPD and PD, is how the preservation of the pylorus in PPPD has been suggested to cause delayed gastric
emptying (DGE) post-operatively, and it has been hypothesised that this is due to operative injuries of the vagus nerve innervating the pyloric region, causing pylorospasms.7
The resection margin of the tumour informs us about if we have achieved radicality or not with the surgical procedure. From the collected histopathological data derived from work done by a dedicated pancreatic pathologist, we can examine whether there is any significant difference in these margins when comparing PPPD and PD.
Objective:
The objective of this paper is identifying potential differences in patients with PDAC that receive either a PD or PPPD in terms of multiple relevant parameters, including
preoperative demographics, perioperative data, post-operative complications, and in particular histological differences in resection margin as well as long-term survival. Through analysing the collected data, an evaluation will be done to determine whether PD or PPPD is a more suitable treatment option in the short and long-term for patients with PDAC.
Method:
From a prospectively maintained hospital database, all patients with a PDAC
presenting to Oslo University Hospital, Rikshospitalet, were identified in the period between January 2016 to December 2017. Patients who had a PDAC that was resectable with either a PD or PPPD were included in this study. Other forms of resection or histopathology will not be included in this study. Patients receiving neoadjuvant chemotherapy will also not be included in this study. This is due to neoadjuvant chemotherapy causing dispersed fibrosis in resected specimens.8 This study has received approval from the hospital review board according to general guidelines from the regional ethics committee, and written informed consent was obtained from all patients involved in the study.
A flowchart illustrating the selection process for this study is shown below.
Figure 1: Flowchart illustrating selection process
Surgical technique:
Patients were evaluated preoperatively in a multidisciplinary setting. This included blood examinations that were taken prior to the surgery, including a pancreatic cancer tumour marker Ca19-9, total serum bilirubin level, albumin level, C-Reactive Protein (CRP).
This preoperative evaluation also involved computed tomography (CT), with standard protocol optimised for pancreatic tumours, and also a CT scan of the chest to evaluate any primary or metastatic tumour sites. Preoperative biliary stenting (PBS) was performed on
patients with symptomatic jaundice, cholangitis, or patients receiving neoadjuvant
chemotherapy (note group receiving chemotherapy is not included in this study).9 The senior surgeon who completed the procedure was also noted during data collection.
As a general rule, PPPD is the preferred method of choice for these resections at OUS, Rikshospitalet. However, it was left to the senior surgeon’s preference to perform a PD in patients where tumour topography or size involved the pylorus, extended towards the distal part of the stomach or where other particular causes warranted that a classical pancreatoduodenectomy was deemed more appropriate. PPPD was performed by dividing the duodenum 2 cm distal to the pylorus and resecting the remaining duodenum distal to this division. Gallbladder and common bile duct are removed. The head, neck, and uncinate process of the pancreas and any periampullary tumour are also removed. For PD, a distal gastrectomy was performed. For both forms of surgery, an end-to-side invaginated
pancreaticojejunostomy was performed, with an end-to-side hepaticojejunstomy. For PPPD, an end-to-side pylorus-jejunostomy was performed, and in PD a side-to-side or an end-to- side gastroenterostomy was performed.10 The two procedures are illustrated below11:
Figure 2: Diagram illustrating surgical technique for PD and PPPD11
The extent of resection for PD is represented by the straight line, and the extent of resection for PPPD is represented by the dotted line.
Definitions:
Severe morbidity was defined as ≥Grade III on the Clavien-Dindo classification of surgical complications. Grade III is defined as a complication requiring surgical, endoscopic, or radiological intervention, Grade IV is defined as a life-threatening complication (including CNS complications) requiring ICU management, and Grade V is defined as the death of a patient.12
Mortality is defined as either a death in-hospital or outside, within 30 days for the 30-day mortality, and within 90 days for 90-day mortality.
Delayed Gastric Emptying (DGE) has three different grades it is defined by, according to the International Study Group of Pancreatic Surgery (ISGPS). This can be illustrated in a table13:
DGE grade Nasogastric tube required
Unable to
tolerate solid oral intake by POD
Vomiting/gastric distension
Use of prokinetics
A 4-7 days or reinsertion
7 ± ±
B 8-14 days or
reinsertion > POD 7
14 + +
C >14 days or
reinsertion > POD 14
21 + +
POD: Postoperative day
Post-pancreatectomy haemorrhage (PPH) is also defined by three different grades by the ISGPS. Grade A PPH occurs when the haemorrhage occurs early (early defined as <24 hours) and having no major clinical impact. Grade B PPH occurs with early severe and delayed (delayed defined as >24 hours) mild cases requiring either transfusion, observation in intermediary care, or intervention. Grade C PPH occurs with delayed, severe haemorrhage requiring intervention and is potentially life-threatening.14
The development of pancreatic leakages and fistulas (PF) are a significant cause of morbidity post-pancreatectomy. PF also has three different grades defined by the ISGPS.15,16
Grade A PF is defined as a “transient fistula” with no clinical impact. It is characterised by no peri-pancreatic collections on CT scan. Little to no change in
management. Patient is clinically well, no sepsis, no prolongation of hospital stay, with slow removal of operatively placed drains.
Grade B PF is a fistula with clinical impact. Characterised by peri-pancreatic drains in place or repositioned to drain collections. Changes in management is required. The patient is clinically well, there is a degree of infection requiring specific treatment, with subsequent prolongation of hospital stay. Patients are often discharged with drains in situ and observed in outpatient setting.
Grade C PF is a fistula with severe clinical impact. Characterised by worrisome peri- pancreatic collections requiring percutaneous drains. Major changes in management
required, often in ICU setting. Some cases may require a re-surgery to salvage the situation.
Patient is clinically unwell. Sepsis is associated with this condition, requiring aggressive antibiotics, octerotides and other intensive care support. Grade C PF is associated with major prolongation of hospital stay, associated complications and possibility of mortality.
Pathological assessment:
Histopathological assessment of the specimens was done by a dedicated pancreatic pathologist. During the pathological assessment, all specimen surfaces were studied systematically from multiple craniocaudal levels throughout the head of the pancreas, instead of taking samples just where it is macroscopically suspected that the tumour resides.17,18 Tumour size in mm was evaluated based on a combined macro- and
microscopical measurement. pT stage (local invasion), and regional lymph node metastasis were both evaluated as according to the UICC TNM 8th edition guidelines from 2016.19 Invasion of peripheral nerves, lympathic vessels, and microvascular structures were evaluated histopathologically. The tumour was also assessed according to its resection margin to other surfaces. These include its margin against the bile duct, the pancreatic neck, proximal gastroduodenal margin, margin to the anterior and posterior surfaces, margin to the superior mesenteric vein (SMV) margin, and the superior mesenteric artery (SMA) margin. R1 resection is defined as tumour cell infiltration within 1 mm of the resection margin as according to the Royal College of Pathologists (UK).20 In accordance with pathology guidelines, the anterior surface is a considered an anatomical surface, not a surgical margin. If the anterior margin is to be considered involved, its surface must be breached by tumour, and thus a clearance of 0 mm is reported as R1 for the anterior surface.18, 21
Statistical methods:
Data analysis was performed using SPSS version 27 for Windows® (IBM, Armonk, New York, USA). All continuous variables in this paper are presented as either a median (range) or mean (standard deviation) dependent on the distribution of data. To compare frequencies and determine significance of differences, the Fisher’s exact test (when frequency was <5 for a data value) or χ2 test (for frequency >5) were applied. For comparison of skewed continuous variables, the Mann-Whitney U test was used. For comparison of data with normal distribution, the two-sample t test was used. For survival analysis, Kaplan-Meier analysis was performed. For multivariate survival analysis, Cox regression was performed. A point-biserial correlation coefficient analysis was performed when one variable was dichotomous, and one variable was continuous. All statistical tests in this paper are two-tailed, and p < 0.050 was considered significant.
Results:
Table 1: Demographic characteristics pre-operation
PD PPPD
Count(n=32) Count(n=43) p-value
Gender Female 15 (46.9%) 27 (62.8%) 0.170
Male 17 (53.1%) 16 (37.2%)
Age, mean (SD)
66.6 (7.48) 67.9 (10.35) 0.552 BMI, mean
(SD)
23.9 (4.68) 24.7 (3.94) 0.449
Type of comorbidity
Diabetes mellitus
6 (31.6%) 5(16.7%) 0.638
Cardiovascular 4 (21.1%) 5 (16.7%) Hypertension 2 (10.5%) 7 (23.3%)
COPD 0 (0.0%) 1 (3.3%)
Other 2 (10.5%) 6 (20.0%)
Multiple comorbidties
5 (26.3%) 6 (20.0%)
ASA score 1 0 (0.0%) 0 (0.0%) 0.006
2 21 (67.7%) 16 (37.2%)
3 9 (29.0%) 27 (62.8%)
4 1 (3.2%) 0 (0.0%)
5 0 (0.0%) 0 (0.0%)
Ca 19-9, preoperative, U/mL, mean(SD)
696.27 (285.02)
729.18 (161.19)
0.915
Albumin,,g/L, mean (SD)
36.6 (5.36) 38.5 (4.26) 0.084
CRP, mg/L, mean(SD)
24.15 (33.4) 16.62 (15.7) 0.282 Preoperative
billiary stent
No 17 (53.1%) 20 (46.5%) 0.571
Yes 15 (46.9%) 23 (53.5%)
Note that with each measure, measurements in bold indicate a significant difference (p<0.05) BMI: Body Mass Index
COPD: Chronic Obstructive Pulmonary Disease ASA: American Society of Anaesthesiologists CRP: C-Reactive Protein
Table 1 shows the demographic characteristics of the two populations receiving either PD or PPPD. The table illustrates that the two populations were comparable with regards to gender (p=0.170). Age was also comparable(p=0.552), with mean age in PD population: 66.6±7.48, and mean age in PPPD population: 67.9±10.35. There was no statistically significant difference in BMI between the two populations (p=0.449), in the PD
population mean BMI was: 23.9±4.68 kg/m2, and mean BMI in the PPPD population:
24.7±3.94 kg/m2. There was no significant difference in comorbidities between the two population groups (p=0.638). There is a statistically significant difference in ASA score between the two populations (p=0.006), with ASA score in the PD population skewed towards ASA 2 (67.7% of PD population), while skewed towards ASA 3 in the PPPD population (62.8% of the population).
Ca 19-9 levels were comparable, with 696.27±285.02 U/mL for the PD population, and 729.18±161.19 U/mL for the PPPD population (p=0.915).
Albumin levels were slightly lower on average in the PD population (36.6±5.36 g/L) than in the PPPD population (38.5±4.26 g/L), but there is no statistically significant
difference in terms of this parameter (p=0.084).
CRP levels were slightly higher on average in the PD population at 24.15±33.4mg/L and in the PPPD population it was 16.62±15.7 mg/L. This was however not a statistically significant difference (p=0.282).
The number of patients with preoperative biliary stents were comparable in the two populations(p=0.571), with 46.9% of the PD population and 53.5% of the PPPD population having this installed.
Table 2: Short-term postoperative complications PD
Count (n=32)
PPPD
Count (n=43) p-value Operative time,
minutes (SD)
404.10(93.1) 356.19(94.7) 0.034 SMV/PV
resection
No 20(62.5%) 31(73.8%) 0.268
Yes 12(37.5%) 11(26.2%)
Arterial resection
No 31(96.9%) 41(97.6%) 0.675
Yes 1(3.1%) 1(2.4%)
Units
transfused, units of SAG,
median(range)
0 (0-4) 0 (0-3) 1
Severe
morbidity (≥III by Clavien- Dindo)
No 28(87.5%) 32(74.4%) 0.244
Yes 4(12.5%) 11(25.6%)
Haemorrhage grade
Grade A 1(3.1%) 4(9.3%) 0.788
Grade B 1(3.1%) 1(2.3%) Grade C 2(6.2%) 2(4.7%)
No 28(87.5%) 36(83.7%)
DGE grade Grade A 6(18.8%) 4 (9.3%) 0.106
Grade B 0(0.0%) 4(9.3%) Grade C 0(0.0%) 2(4.7%)
No 26(81.2%) 33(76.7%)
PF grade Grade A 1(3.1%) 5(11.6%) 0.091
Grade B 0(0.0%) 2(4.7%) Grade C 0(0.0%) 1(2.3%)
No 31(96.9%) 35(81.4%)
Length of hospital stay, days, mean(SD)
9.1 (6.96) 11.5(17.8) 0.472
ICU stay, days, mean (SD)
1.03(0.18) 1.35(0.97) 0.073
30-day mortality No 32 (100.0%) 43 (100.0%) 1
Yes 0 (0.0%) 0 (0.0%)
90-day mortality No 31 (96.9%) 43(100.0%) 0.427
Yes 1(3.1%) 0(0.0%)
Readmission (90-day)
No 27 34 0.560
Yes 5 9
Note that with each measure, measurements in bold indicate a significant difference (p< 0.05) DGE: Delayed Gastric Empyting
PF: Pancreatic Fistula ICU: Intensive Care Unit
Table 2 primarily illustrates the short-term postoperative complications in the two populations. The first parameter the table shows however, is the total operative time. There is a statistically significant difference (p=0.034) between the two populations with respect to the operative time. In PD, the mean operative time was 404.10±93.1 minutes, and in PPPD the mean operative time was 356.19±94.7 minutes.
Resection of the SMV/PV during surgery was also recorded for both populations. For the PD population, SMV/PV resection occurred during 37.5% of surgeries, and for the PPPD population SMV/PV resection occurred during 26.2% of the surgeries. There was no
statistically significant difference between the two populations in terms of SMV/PV resection (p=0.268).
Arterial resection occurred in 3.1% of surgeries in the PD population, and for 2.4% of the surgeries in the PPPD population. This was not a statistically significant difference between the two populations(p=0.675).
Do note that for both SMV/PV and arterial resection, data was not found for one patient that received a PPPD surgery.
Another parameter is units transfused measured in units of SAG. For the PD
population the median was 0 units of SAG (range 0-4 units), and for the PPPD population the median was again 0 units of SAG (range 0-3 units). There was no statistical significance between the two populations for this parameter (p=1).
The proportion of patients that had severe morbidity (defined as ≥III by Clavien- Dindo) associated was 12.5% in the PD population and 25.6% in the PPPD population. This is a slight difference in the population but is not statistically significant (p=0.244).
Haemorrhage grade in the two populations is similar, with no statistically significant difference (p=0.788). 87.5% of the PD population and 83.7% of the PPPD population had no post-pancreatectomy haemorrhage. The distribution of more serious post-pancreatectomy haemorrhage (Grade A, Grade B, and Grade C) was similar in both populations, see table 2.
DGE in the two populations is also relatively similar. 81.2% of the PD population and 76.7% of the PPPD population had no DGE. DGE grade A was similar in both populations,
with 18.8% in the PD population and 9.3% in the PPPD population. However the table shows a higher incidence of more severe DGE (Grade B and Grade C) in the PPPD population, with 9.3% having Grade B DGE and 4.7% having Grade C DGE in the PPPD population, in contrast to 0 having either Grade B or C in the PD population. The difference between the two populations was not statistically significant (p=0.106).
For PF, we see that 96.9% of the PD population and 81.4% of the PPPD population had no degree of PF. However, only 1 patient (3.1%) of the PD population had PF (This was Grade A PF). In the PPPD population, 11.6% of the population had Grade A PF, 4.7% had Grade B PF, 2.3% had Grade C PF. Although the difference between these two populations was not statistically significant (p=0.091), it illustrates a potential difference that will be discussed further later in this paper.
Total length of hospital stay was similar in both populations. For PD, the mean length of hospital stay was 9.1±6.96 days, and for PPPD this was slightly higher at 11.5±17.8 days.
No statistically significant difference between the two populations for this parameter (p=0.472).
The length of ICU stay is comparable in the two populations. In PD, the mean length of ICU stay is 1.03±0.18 days, and in PPPD the mean length of ICU stay is 1.35±0.97 days.
There is no statistically significant difference in length of ICU stay between the two populations (p=0.073).
In both populations there were no deaths that occurred 30 days post-operation.
In terms of 90-day mortality, in the PD population 1 patient (3.1%) died, and in the PPPD population there were no deaths within 90 days post-operation. Long-term mortality will be presented in a later figure.
Table 3: Distribution of surgeons performing either PD or PPPD
PD PPPD p-value
Surgeon 1 14(43.8%) 7(16.7%) <0.001
Surgeon 2 6(18.8%) 0(0%)
Surgeon 3 0(0%) 2(4.8%)
Surgeon 4 0(0%) 14(33.3%)
Surgeon 5 5(15.6%) 5(11.9%)
Surgeon 6 5(15.6%) 12(28.6%)
Surgeon 7 2(6.3%) 2(4.8%)
Note that with each measure, measurements in bold indicate a significant difference (p< 0.05)
*1 missing value in the PPPD population
Above is a table which illustrates what form of surgery, PD or PPPD, has been performed by the seven senior surgeons who performed such surgeries at OUS,
Rikshospitalet during the period studied. Surgeon 1 performed 43.8% of the PD surgeries and 16.7% of the PPPD surgeries. Surgeon 2, however, performed 18.8% of the PD surgeries and none of the PPPD surgeries. Surgeon 3 performed none of the PD surgeries and 4.8% of the PPPD operations. Surgeon 4 performed none of the PD surgeries and 33.3% of the PPPD surgeries. Surgeon 5 performed 15.6% of the PD surgeries and 11.9% of the PPPD surgeries.
Surgeon 6 performed 15.6% of the PD surgeries and 28.6% of the PPPD surgeries. Surgeon 7 performed 6.3% of the PD surgeries and 4.8% of the PPPD surgeries. There was a statistically significant difference(p<0.001) between which surgeon was the one who operated on the patient and what form of surgery was performed.
Table 4: Histopathological characteristics of the tumour
PD PPPD
Count (n=32)
Count (n=43)
p-value Tumour size,
mm, median (range)
38 (23-55) 35 (21-58) 0.303
pT-stage pT1 0 (0.0%) 0(0.0%) 0.573
pT2 0(0.0%) 1(2.3%) pT3 32 (100.0%) 42(97.7%) Number of
positive lymph nodes, mean (SD)
6.06 (4.77) 4.70 (3.46) 0.155
Lymph node ratio, mean (SD)
0.28(0.20) 0.27(0.21) 0.875
Perineural invasion
No 0(0.0%) 3(7.0%) 0.256
Yes 32(100.0%) 40(93.0%) Lymphatic
vessel invasion
No 1 (3.1%) 4 (9.3%) 0.386 Yes 31(96.9%) 39 (90.7%)
Vascular invasion
No 4 (12.5%) 8 (18.6%) 0.540 Yes 28(87.5%) 35 (81.4%)
Note that with each measure, measurements in bold indicate a significant difference (p<0.05)
Table 4 illustrates the histopathological characteristics of the tumour and compares these characteristics between the two populations we are investigating. Tumour size in both populations is comparable; PD has median tumour size of 38mm(23-55mm), and PPPD has median tumour size of 35 (21-58). No statistically significant difference between the two populations in terms of tumour size (p=0.303).
In terms of pT-stage, the two populations were comparable. In the PD population, 100.0% had a pT3, while in the PPPD population, 97.7% had a pT3, while 1 patient (2.3%) had a pT2. No statistically significant difference between the two populations in pT stage (p=0.573).
The mean number of positive lymph nodes in the PD population was 6.06±4.77, and in the PPPD population the median was 4.70±3.46. No statistically significant difference between the two populations (p=0.155).
Lymph node ratio in the two populations was also comparable, in the PD population the mean was 0.28±0.20, and in the PPPD population the mean was 0.27±0.21. No
statistically significant difference between the two populations (p=0.875).
100.0% of the PD population has perineural invasion by the tumour during histopathological examination. In the PPPD population, 93.0% of the patients have perineural invasion, while 3 patients (7.0%) did not have this. No statistically significant difference between the two populations (p=0.256).
Lymphatic vessel invasion in the two populations is comparable, with 96.9% in the PD population having this, and 90.7% of the PPPD population having lymphatic vessel invasion.
No statistically significant difference between the two populations (p=0.386)
Vascular invasion was present in 87.5% of the PD population, and in 81.4% of the PPPD population. No statistically significant difference between the two populations (p=0.540).
Table 5: Resection margin for PD vs PPPD
PD PPPD
Count (n=32) Count (n=43) p-value
Bile duct margin R0 31 (96.9%) 42 (97.7%) 0.675
R1 1 (3.1%) 1 (2.3%)
Proximal gastric- duodenal margin
R0 32 (100.0%) 43(100.0%) 1.000
R1 0 (0.0%) 0(0.0%)
Pancreatic neck margin
R0 27 (84.4%) 39(90.7%) 0.484
R1 5 (15.6%) 4(9.3%)
Anterior surface R0 28 (87.5%) 36 (83.7%) 0.749
R1 4 (12.5%) 7 (16.3%)
Posterior surface R0 19 (59.4%) 29 (67.4%) 0.472
R1 13 (40.6%) 14 (32.6%)
SMV margin R0 7 (21.9%) 20 (46.5%) 0.028
R1 25 (78.1%) 23 (53.5%)
SMA margin R0 10 (31.3%) 28 (65.1%) 0.004
R1 22 (68.8%) 15 (34.9%) Overall margin
status
R0 R1
3 (11.1%) 29 (88.9%)
10 (20.0%) 33 (80.0%)
0.136 Number of
margins
involved, mean (SD)
2.19 (1.39) 1.49(0.96) 0.011
Note that with each measure, measurements in bold indicate a significant difference (p< 0.05)
Table 5 illustrates how the two populations receiving either PD or PPPD differed in terms of resection margins. As explained in the method section, there are 6 unique resection margins that are relevant in determining whether surgical radicality has been achieved or not. One such margin is the bile duct margin. In both PD and PPPD populations, 3.1% and 2.3% respectively achieved a R1 margin for this resection margin. There is no statistically significant difference in this resection margin between the two populations (p=0.675).
There is no involvement of the proximal gastric-duodenal margin for both the PD or PPPD population, and thus there is no statistically significant difference between the two populations with regards to this margin (p=1.000).
The pancreatic neck margin is another resection margin that must be considered. For the PD population, 15.6% had a R1 margin (84.4% with R0 margin), and for the PPPD
population, 9.3% (90.7% with R0 margin) had a R1 margin. There was no statistically significant difference between the PD and PPPD population in terms of this margin (p=0.484).
Similarly, we can look at the anterior surface margin, where 12.5% in the PD
population had a R1 margin (87.5% with R0 margin), and 16.3% in the PPPD population had a R1 margin (83.7% with R0 margin). No statistically significant difference between the two populations (p=0.749).
In relation to the posterior surface margin, 40.6% of the PD population had a R1 margin (59.4% with R0 margin), and 32.6% of the PPPD population had a R1 margin (67.4%
with R0 margin). Again, there is no statistically significant difference between the two populations (p=0.472).
For the SMV margin, 78.1% of the PD population had a R1 margin (21.9% with R0 margin), and 53.5% of the PPPD population had a R1 margin (46.6% with R0 margin). The difference is statistically significant (p=0.028). This will be discussed and considered in greater detail in the discussion section of this paper.
We can also look at the SMA margin, with 68.8% of the PD population having a R1 margin (31.3% with R0 margin). For the PPPD population, 34.9% have a R1 margin (65.1%
with R0 margin). This difference between the two populations is statistically significant (p=0.004). This finding, especially seen in correlation with the SMV margin, indicates a relationship between the two population types and the resection margin towards vascular structures. This will again be considered in greater detail in the discussion section of this paper.
For a better overview, we can also look at the overall margin status and compare the two populations with regard to this. In the PD population, 88.9% had a R1 overall margin status (11.1% with R0 overall margin status), and in the PPPD population 80.0% had a R1 overall margin status (20.0% with R0 overall margin status). There was no statistically significant difference between the two populations with regards to overall margin status (p=0.136).
In addition to overall margin status we can also look at the total number of margins involved. For the PD population, the mean number of margins involved was 2.19±1.39, and for the PPPD population the mean number of margins involved was 1.49±0.96. This gave a statistically significant difference (p=0.011). This finding will also be discussed in further detail later in this paper.
Figure 3: Kaplan-Meier survival plot for PD vs PPPD
Numbers at risk
PD 32 23 15 13 11
PPPD 43 31 18 12 6
Illustrated above is a Kaplan-Meier survival plot, showing how the cumulative
survival varies with months survived post-surgery. The estimated median survival for the PD group is 20.0 months (range: 2-59 months), and the median survival for the PPPD group was 20.0 months (range: 3-50 months). The log-rank (Mantel-Cox) was 0.914, thus the difference between the two groups in terms of long-term survival was not statistically significant.
The three-year survival for both the PD and PPPD population was also found. For the PD population, 11 out of 32 patients (34.4%), and for the PPPD population 12 out of 43 patients (27.9%) had survived three years post-operation
Figure 4: Kaplan-Meier survival plot for PD comparing overall margin status
Numbers at risk
R0 3 3 2 0 0
R1 29 20 13 13 11
Illustrated above is a Kaplan-Meier plot, showing how cumulative survival within the PD population varies with overall margin status. The estimated median survival for patients with overall margin status R0 was 28.0 months (range:20-31 months), and for the R1 population was 19.0 months (range 2-59 months). There was no statistically significant difference between R0 and R1 margin status in terms of survival (p=0.838).
Figure 5: Kaplan-Meier survival plot for PPPD comparing overall margin status
Numbers at risk
R0 10 7 6 6 4
R1 33 24 12 11 2
Illustrated above is a Kaplan-Meier plot, showing how cumulative survival within the PPPD population varies with overall margin status. The estimated median survival for patients with overall margin status R0 was 33.0 months (range 5-50 months), and for the R1 population was 19.0 months (range 3-50 months). There was no statistically significant difference between R0 and R1 margin status in terms of survival (p=0.221)
A multivariate Cox regression analysis was also performed to see if the involvement of the SMV, SMA margins, total number of margins involved, and overall margin status respectively impacted survival within either PD or PPPD population, as past literature would have suggested.
For the PD population, this analysis yielded a hazard ratio for the SMV margin of 5.12 (95% CI: (0.96, 29.79), p=0.102), for the SMA margin 2.05(95% CI: (0.54, 6.46), p=0.307), for total number of margins involved 2.43 (95% CI: (1.26, 4.04), p=0.005) and for the overall
margin status 1.42 (95% CI: (0.15, 6.87), p=0.850). Thus there was a statistically significant relationship between the total number of margins involved and survival, and for SMV there seems to be a strong association with a positive SMV margin and overall survival albeit not a statistically significant relationship, SMA, and overall margin status and long-term survival in the PD population.
Similarly, for the PPPD population; the analysis gave a hazard ratio for the SMV margin of 1.30 (95% CI: (0.52, 3.13), p=0.571), for the SMA margin 1.67 (95% CI: (0.65, 4.11), p=0.287), for total number of margins involved 1.21 (95% CI: (0.64, 2.34), p=0.564) and for the overall margin status 0.57 (95% CI: (0.14, 2.48), p=0.468). Thus, in the PPPD population, there was no statistically significant relationship between SMV, SMA, total number of margins involved, overall margin status and long-term survival.
A point-biserial correlation analysis was performed between tumour size and involvement of the SMV margin. This yielded a statistically significant correlation (p=0.001) between tumour size and involvement of the SMV margin.
Discussion:
This section of the paper will first discuss and analyse the relevant points and findings from the results section. This discussion will then be utilised to try to elucidate what
differences, if any, exist between the two populations that receive either PD or PPPD, and to see if PD or PPPD is a more suitable treatment option in the short-term and long-term for patients with PDAC.
From table 1, there were no statistically significant differences between the two populations in terms of demographics and pre-operative characteristics, including gender, age, BMI, comorbidities, Ca 19-9 values, albumin, CRP, and pre-operative biliary stenting between the two populations, which would suggest that overall the two populations of patients are comparable pre-operatively.
However, from the data, an ASA score of 2 was obtained by 67.7% of the PD
population and 37.2% of the PPPD population, and an ASA score of 3 was obtained by 29.0%
of the PD population and 62.8% of the PPPD population. This was a statistically significant difference(p=0.006) and would indicate that the PPPD population has a higher proportion of patients with a higher ASA score. The significance of this finding is unclear, as ASA score is correlated with the comorbidities of the patients, and statistical analysis showed no
statistically significant difference between the two populations in terms of that parameter (p=0.638). However, a study that evaluated postoperative outcomes of patients receiving laparoscopic distal pancreatectomy (LDP) came to the conclusion that postoperative outcome and complications are similar between patients that have a higher ASA score and thus higher anaesthetic risk as compared to patients with a lower ASA score. Although this study involved a procedure that is less invasive than PD or PPPD, it gives an indication that this difference in ASA score should not play a significant role in outcome post-operatively.22
From table 2, there was a statistically significant difference between the two populations in terms of operative time (p=0.034), with the mean operative time in the PD population being 404.10±93.1 minutes, and in PPPD the mean operative time was
356.19±94.7 minutes. In a meta-analysis comparing PD to PPPD in terms of peri-operative complications, there was no such statistically significant difference between PD and PPPD with regards to operative time.23, 24 Thus, it is difficult to draw any strong conclusions from this finding as it could simply be a result of a small sample size.
There was no statistically significant difference between the two populations in terms of SMV/PV resection (p=0.268), with resection occurring in 12 out of 32 cases in the PD population and in 11 out of 43 cases in the PPPD population. After extensive searching, there was no earlier literature that compared the incidence of SMV/PV resection in the PD and PPPD population.
Arterial resection was another component that was compared between the two populations. There was no statistically significant difference between the two populations with regards to arterial resection(p=0.675), with 1 out of 32 patients in the PD population and 1 out of 42 patients in the PPPD population having arterial resection done. Similarly, to above, no earlier literature has compared the incidence of arterial resection in the PD and PPPD population respectively.
There is no statistically significant difference between the two populations in terms of units transfused, severe morbidity (≥3 by Clavien-Dindo), and haemorrhage grade. As discussed earlier, it has been hypothesised that PPPD has a higher incidence of DGE due to operative injuries of the vagus nerve innervating the pyloric region, causing pylorospasms to occur.7 However, from this data there was no statistically significant difference between the two populations in terms of this parameter (p=0.106). In terms of PF grade, the PD
population had 1 out of 32 patients with grade A PF, and the PPPD population had 5 out of
43 patients with grade A PF, 2 of 43 with grade B PF, and 1 out of 43 with grade C PF. There was no statistically significant difference between the two populations with regards to pancreatic fistulas(p=0.091).
It should be noted that for both the populations the incidence of PF was relatively small. A study has been made to validate a risk score model based on the texture of the pancreas to predict the incidence of PF after pancreatoduodenectomy.25 From this study, a statistically significant relationship between an intra-operatively evaluated pancreatic texture and the incidence of PF was found, with a hard textured pancreas having a lower incidence of PF. This may be an explaining factor as to why the incidence of PF was small in the PD and PPPD populations as PDAC tumours tend to be of hard texture. PDAC tumours also tend to cause a dilation of the pancreatic duct (duct of Wirsung), and this referened study verified the relationship between a dilated duct and lower incidence of PF.25
There was no statistically significant difference between the two populations in terms of length of hospital stay, ICU stay, 30-day mortality and 90-day mortality. These findings from table 2 are consistent with subgroup analysis of three RCT’s in a meta-analysis, which also showed no statistically significant differences between their PD and PPPD
population with regards to DGE, pancreatic fistula, post pancreatectomy haemorrhage, intra-abdominal fluid collection/abscess, bile leakage, perioperative blood loss, duration of operation and length of hospital stay.23,26,27,28
Table 3 illustrates the distribution of surgeons that perform either a PD or PPPD.
There was a statistically significant difference (p<0.001) between the operating surgeon and what form of operation was performed (either PD or PPPD). This could indicate some inherent bias within the study, for example surgeon 2 performed 18.8% of the PD surgeries whereas performing none of the PPPD surgeries, even though as stated in the surgical method section the guideline at OUS, Rikshospitalet is to generally perform PPPD, unless other factors such as tumour topography or involvement of the pylorus were present in which case a PD was performed. This bias can interfere with any other relationship that is found between what form of surgery is performed and other parameters and should be kept in mind when evaluating the results in this study.
Table 4 shows the histopathological characteristics of the tumour for the PD and PPPD population. One characteristic is the slight difference in tumour size. In the PD
population, the median tumour size is 38 mm (23mm-55mm), and for the PPPD population the median tumour size is 35 mm(21mm-58mm). This was not a statistically significant relationship (p=0.303), however, there is a slight difference in tumour size that may help explain certain differences between the two populations in particular with regards to the involvement of certain resection margins. This is expanded upon later in this discussion.
There was no statistically significant difference between the two populations in terms of pT-stage, number of positive lymph nodes, or lymph node ratio. In terms of the direct pathological characteristics of the tumours, there was no statistically significant difference between the populations in terms of perineural invasion, lymphatic vessel invasion, and vascular invasion.
Table 5 illustrated the resection margins for the PD and PPPD population. One such margin is the proximal gastric-duodenal margin. This margin is the main difference between PD and PPPD surgery, as in PD surgery the gastric segment of this margin is removed and in PPPD surgery this gastric segment is preserved. From the table, it is clear that for both PD and PPPD populations, 100.0% achieved a R0 margin for the proximal gastric-duodenal margin (giving a p=1.000). This indicates that there is no significant difference in radicality between the two different procedures in terms of this resection margin.
There was a statistically significant difference in terms of the SMV margin (p=0.028), with 25 out of 32 (78.1%) patients in the PD population with a microscopic margin
involvement R1, while 23 out of 43 (53.5%) in the PPPD population had a R1 involvement of the SMV margin. Before discussing this finding further, it is important to clarify certain anatomical factors around this specific margin. The microanatomy at this margin is such that the groove of the SMV lies directly over the pancreatic parenchyma without a layer of
adipose tissue separating the SMV-groove from the pancreas. Additionally, the fibrous tissue that lies under the SMV-groove is exceptionally thin. Having such an anatomy at this margin, means that there becomes an excruciatingly small difference between a tumour that
infiltrates into the venous wall, and thus has a R1 margin, and a tumour that is >1 mm away from the SMV-groove and thus a R0 margin.18 This could explain the high rate of
involvement of the SMV margin for both populations. This is also of course exacerbated by the intrinsic invasive nature of PDAC as was illustrated in table 4.
It is difficult to determine exactly why the PD population has a statistically significant higher rate of R1 resection at the SMV margin compared to the PPPD population, however,
this could perhaps be explained by the anatomic nature of the tumour itself. As we saw in table 2, although not a statistically significant difference (p=0.303), the median tumour size in the PD population was 38 mm (range:23 mm-55 mm) and in the PPPD population was 35 mm (range:21 mm-58 mm). This slightly larger tumour size for patients receiving PD may be an explaining factor for this difference in SMV margin between the two populations. This is supported by the statistically significant point-biserial correlation (p=0.001) between tumour size and involvement of the SMV margin.
Another factor that is relevant is the exact location of the tumour, as tumours that are located near this margin could have a higher probability of being involved in the respective margin. There was no data collected for this paper pertaining to this factor, however if mapping of tumour location using a CT scan was performed pre-operatively then perhaps an association between location of tumour and margin involvement could be determined, and this would be an interesting investigation to take further in a different paper.
This relationship could also come about as a result of the general guideline at OUS, Rikshospitalet that PPPD is to be performed unless tumour topography or involvement of pylorus/stomach was such that a PD must be performed. This was also seen in table 3, which indicated a statistically significant relationship between the individual surgeon and what form of surgery was performed. As a result, the relatively fewer times surgeons performed a PD as compared to performing PPPD, it could be more likely that tumour topography is such in PD that there is involvement of margins such as the SMV margin, thus yielding this
statistically significant relationship between PD surgery and involvement of the SMV margin.
Additionally, from table 2 it is clear that there is no statistically significant difference between the two populations with regards to SMV/PV resection. One would expect that with a significant relationship with involvement of the SMV margin during PD surgery, that there would also be a significant relationship between SMV/PV resection and PD surgery, but this is not the case.
Another aspect to take note of, is that the two populations studied here had a quite large proportion of patients with a positive SMV margin, with 78.1% in the PD population and 53.5% in the PPPD population. This proportion is smaller in a multicentre study involving 531 patients, where 29.7% of the patients had involvement of the SMV margin.29 It is
difficult to make a conclusive argument as to why this is the case, however, it could indicate
that perhaps the sample size that is presented in this paper is skewed towards potentially larger tumours or tumours that are located in such a way that SMV margin involvement is more likely, which thus gives the higher proportion of SMV involvement that is seen here.
There is also the possibility that individual pathological assessment can be a contributing factor to this as well.
There was also a statistically significant difference between the two populations in terms of the SMA margin (p=0.004). 22 out of 32(68.8%) patients that received PD had microscopic/R1 involvement of the SMA margin, and 15 out of 43(34.9%) patients that received PPPD, had microscopic involvement of the SMA margin. Do note that the relatively common involvement of the SMA margin for both PD and PPPD populations is in line with the same multicentre study mentioned above, which has described the SMA margin as the most commonly involved margin, with about 43.6% of all patients having a tumour with SMA margin involvement.29
From table 5 there is also a statistically significant difference between the two populations in terms of the total number of margins involved, with the mean number of margins involved in the PD population being 2.19 (±1.39) margins, while in the PPPD population the mean number of margins involved was 1.49 (±0.96) margins (p=0.011).
Overall margin status is another parameter that was investigated. From the data, we see that in the PD population 29 out of 32 patients had a R1 overall resection, while in the PPPD population 33 out of 43 patients achieved a R1 overall resection. There was not a statistically significant difference between the two populations with regards to overall margin status (p=0.136).
The involvement of both the SMV and SMA margins, total number of margins involved, and the overall margin status is thought to be significant in terms of survival of patients that have PDAC. An earlier multicentre study including 150 patients had indicated that positive SMV and SMA margins has a statistically significant effect on two-year
progression free survival (PFS).30 Another multicentre study involving 531 patients, had found that the involvement of the SMA margin is a particularly negative prognostic factor for patients, as the involvement of this margin lead to the worst outcome in survival as
compared to involvement of any other margins.29 The two findings described above and their inherent clinical significance illustrates a key difference between PD and PDAC in terms
of long-term patient survival, and if we take this in isolation we would also subsequently expect to see a significant difference in long-term survival in the two populations.
Interestingly enough, Figure 3 illustrates that this is not the case in our data sample.
The estimated median survival for the PD group was 20.0 months (range: 2-59 months), and for the PPPD group was 20.0 months (range: 3-50 months). The log-rank (Mantel-Cox) was 0.914, and thus there is no statistically significant difference in long-term survival between the two populations receiving either PD or PPPD.
Furthermore, to see if involvement of the SMV, SMA margins, total number of margins involved, and overall margin status respectively impacted survival within either the PD or PPPD population, a Cox regression analysis was performed as shown in the results section.
For the PD population, there was a statistically significant relationship between the total number of margins involved(p=0.005) and survival. There was no statistically significant relationship between SMA (p=0.307), SMV (p=0.102), overall margin status(p=0.850) and long-term survival in the PD population.
For the PPPD population, there was no statistically significant relationship between SMV (p=0.571), SMA(p=0.287), total number of margins involved (p=0.564), overall margin status (p=0.468) and long-term survival.
From Figure 4 we can further evaluate how overall margin status impacts survival in the PD population. The estimated median survival for patients with overall margin status R0 was 28.0 months (range: 20-31 months) and for patients with overall margin status R1 this was 9.0 months (range: 2-59 months). However, there was no statistically significant difference in survival between patients with a R0 overall margin status and patients with a R1 overall margin status (p=0.838). It should be kept in mind however, that there were only three patients in the PD population with a R0 overall margin status, and as a result of this small sample size the relationship between survival and overall margin status in this population may be distorted.
This analysis can also be repeated for Figure 5, which evaluates the impact of overall margin status on the PPPD population. From this, the estimated median survival for patients with overall margin status R0 was 33.0 months (range: 5-50 months), and for the 19.0 months (range: 3-50 months) for patients with overall margin status R1. There was no statistically significant difference in survival between these two groups in terms of survival
(p=0.221). However, similarly as what was seen in Figure 4, there remains a significant gap in estimated median survival between the two different overall margin statuses, with a higher estimated median survival in the R0 population. This is in line with findings from other studies, including one multicenter study involving 305 patients investigating the impact of resection margin status on survival in pancreatic cancer patients. This study found that patients that achieved a negative overall margin status, R0, had a statistically significant longer overall survival than patients that had a positive resection margin R1 (p <0.001).31
Thus, to summarise the discussion about resection margin in the two populations and how this relates to long-term survival, there was a statistically significant relationship in the PD population between total number of margins involved and survival, however, there was not significant difference for patients who have a positive SMV, SMA, or overall margin status in both the PD and PPPD populations.
These findings are at a crossroads with results from other studies30 which indicate a significant relationship between positive SMV and SMA margins and patient survival. Thus, although a significant relationship was found between a higher incidence of positive SMV and SMA margins within the PD population, the relevance of this relationship is diminished as it does not appear to have significance in terms of survival. That is not to say the finding has no clinical significance at all, however, due to a lack of data pertaining to quality of life of patients or tumour relapse for example, it is difficult to say exactly what significance this finding has.
Further investigation and limitations:
One important limitation of this paper that is essential to consider, pertains to the fact that this is a retrospective analysis of data. Due to the retrospective nature of the analysis, there may be inherent biases in the results as there has not been a randomisation process for patients to receive either a PD or PPPD. This could for example impact the significant relationship seen between patients receiving PD and having a positive SMV or SMA margin, as the surgeons are might have been more likely to select a PD than a PPPD when seeing a tumour that is located in the pancreas that may be larger and more medially located; and conversely selecting a PPPD might have been viewed as being a less suitable form of surgery for such patients. It would be quite intriguing to see if this significant
relationship would still exist if the patients were randomised to either receive a PD or PPPD.
Also, procedures performed by the individual surgeons, as illustrated in table 3, revealed that two surgeons only performed PD or PPPD, respectively. This could be due to
macroscopic findings per-operatively, but an individual surgeon’s preference towards one of the two procedures could also be present, limiting the findings in this audit.
Another clear limitation to this paper is the limited size of the study, and this makes it more difficult to make any definitive conclusions from the data and subsequent analysis of this data. However, this limited size was due to a number of exclusion criteria highlighted in Figure 1, and this exclusion process did ensure that the cohorts of patients were relatively similar in both populations.
Although this was mentioned earlier in the discussion, an important investigation that should be conducted in the future is determining the exact topography of the tumour in the pancreas and of its surroundings, and this could be done through CT scanning for
example. This would likely allow for a more detailed analysis and explanation as to why there was a statistically significant difference between the PD and PPPD population with regards to SMV and SMA resection margins; thus enabling an answer to a greater extent to a central question within this particular paper.
Conclusion:
To conclude, there were no significant differences in terms of demographic characteristics, post-operative complications, morbidity, and survival that are relevant to distinguishing between PD and PPPD. However, in the PD population, there are statistically significantly more positive SMA and SMV resection margins, in addition to more total number of margins involved. Albeit the fact that within this study only the number of margins involved results in a significant impact on survival, the impact of the positive SMA and SMV resection margins should be investigated further in a randomised study to see if these are actual differences between the two populations and look further to see if these differences have an actual impact on patient outcome.
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