comparing laparoscopic and open pancreaticoduodenectomy in ... · accepted article this article is...

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This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/JHBP.697

This article is protected by copyright. All rights reserved

Comparing Laparoscopic and Open Pancreaticoduodenectomy in Patients with Pancreatic Head Cancer: Oncologic outcomes and Inflammatory Scores

Munseok Choi, M.D. 1,2,3, Ho Kyoung Hwang, M.D. Ph.D. 1,2,3, Seoung Yoon Rho, M.D. 1,2,3, Woo Jung Lee,

M.D., Ph.D. 1,2,3, Chang Moo Kang, M.D., Ph.D. 1,2,3

Division of Hepatobiliary and Pancreatic Surgery1, Department of Surgery2, Yonsei University College of

Medicine

Pancreatobiliary Cancer Center3, Yonsei Cancer Center, Severance Hospital, Seoul, Korea

Key Words: laparoscopy, pancreaticoduodenectomy, disease free survival, inflammation, pancreatic

cancer

List of word count : abstract 194, introduction 333, Methods 272, Results 476, Discussion 691

Table counts : 5

Figure counts : 2

Corresponding Author

Chang Moo Kang, M.D., Ph.D.

Department of Surgery, Yonsei University College of Medicine

Ludlow Faculty Research Building #203

50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Korea

Fax: 82-2-313-8289, Tel: 82-2-2228-2135, E-mail: [email protected]

Abstract

Background/Purpose: Both the technical and oncological safety of laparoscopic

pancreaticoduodenectomy (LPD) remain controversial in treating pancreatic head cancer. We evaluated

the oncologic benefit of LPD and compared the inflammatory score between LPD and open

pancreaticoduodenectomy (OPD).

https://doi.org/10.1002/JHBP.697

https://doi.org/10.1002/JHBP.697

mailto:[email protected]

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Methods: From January 2014 to March 2019, 61 patients with standard PD not combined with other organ

resection were finally enrolled in this study. Among these patients, 27 underwent LPD and 34 underwent

OPD. (registered on July 16th , 2019, and registration number is 2019-1411-001)

Results: The estimated blood loss (EBL) for the LPD group was less than that of the OPD group

(p=0.003). The operation time was similar, as was the incidence of complications such as postoperative

fistula, delayed gastric emptying. Overall survival was not different between LPD and OPD (44.62 vs 45.29

months, p=0.223). However, a significant improvement in disease-free survival (DFS) was seen in the LPD

group (34.19 vs 23.27 months, p=0.027). No statistically significant differences were found in terms of the

postoperative change in inflammatory scores and differentiated WBC counts.

Conclusions: LPD is not only safe and feasible in pancreatic head cancer patients but is associated with a

reduced amount of EBL, favorable DFS.

Introduction

Pancreatic cancer is one of the most fatal diseases of the gastrointestinal tract and is projected to become

the second leading cause of cancer-related death by 2030. [1] Surgical resection remains the only

potentially curative treatment for pancreatic cancer, and resection with clear microscopic margins is the

only curative treatment for pancreatic cancer. [2,3] Since its first trial by Gagner and Pomp in 1994, the

minimally invasive approach for pancreaticoduodenectomy (PD) has been evolving for decades despite the

complex intra-abdominal dissection and reconstruction techniques. [4]

Laparoscopic PD (LPD) has been shown to have several advantages in short-term oncologic outcomes,

such as lower intraoperative blood loss and transfusion, fewer postoperative morbidities, higher lymph node

retrieval, and shortened hospital stays. [5,6] Even regarding long-term oncologic outcomes, LPD for

pancreatic head cancer has demonstrated better progression-free survival and disease-free survival than

OPD. [7,8] Potential reasons include the reduction in physiological and immunological effects of LPD and

timely adjuvant chemotherapy in patients with pancreatic head cancer. [7]

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An increased systemic inflammatory response after 24 hours of surgery is associated with postoperative

complications, [9,10] and much evidence has also suggested that the oncologic outcome is influenced not

only by tumor behavior but also by the host response through systemic inflammation. [11,12] Additionally,

several systemic inflammation-based scores, such as the total lymphocyte count, neutrophil-to-lymphocyte

ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR), have been

proposed as prognostic factors for several cancers, including pancreatic cancer. [13-15] It has been

thought that minimally invasive surgery may reduce surgical trauma and the inflammatory response. Thus,

the reduced inflammatory response could be a clue to explain why LPD has shown a better long-term

oncologic outcome than OPD. However, the recent suspended randomized control trial (LEOPARD-2 trial)

for LPD revealed no significant difference between the LPD and OPD groups. [16]

Therefore, this study was performed 1) to determine whether there is benefit in the short-term operative

outcome and long-term oncologic outcome and 2) to directly compare the postoperative time-dependent

inflammatory scores between the LPD and OPD groups in treating pancreatic head cancer.

Methods

Patients and data collection

This study was approved by the Institutional Review Board of Yonsei University College of Medicine

(registered on July 16th , 2019, and registration number is 2019-1411-001). From January 2014 to March

2019, the medical records of 111 patients who underwent pylorus-preserving PD (PPPD) for pancreatic

head cancer by a single surgeon were retrospectively reviewed. To homogenize the patient’s

characteristics, patients with the following clinical conditions were excluded in the final analysis: those who

underwent 1) neoadjuvant chemo ± radiation therapy, 2) vascular resection during operation, and 3) open

conversion (Fig.1).

Surgical methods

In reconstruction phase, all PPPD procedure was conducted using end to-side pancreaticojejunostomy, an

end-to-side hepaticojejunostomy, and side-to- side duodenojejunostomy. The details of all procedures are

described in the previously reported literature. [4,17,18] Selection criteria for LPD consisted of patients who

have good general condition capable for enduring long-time pneumoperitoneum and no severe obesity, no

expecting combined vascular resection and resectable pancreatic cancer with clear fat line between tumor

and vascular interfaces, which can be managed by standard PD.

Assessment of postoperative time-dependent inflammatory scores

The inflammation scores in this study included LMR, NLR, and PLR and were calculated using standard

laboratory blood test results performed before surgery, postoperative day 0, 3, 5, 7, and one day before

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discharge. The white blood cell (WBC) count, such as the neutrophil, lymphocyte, monocyte, and platelet

counts, were collected in the same manner. The collected data were analyzed using the linear mixed

model.

Statistical analysis

All statistical analyses were performed using SPSS Statistical software (version 23.0, SPSS Inc., Chicago,

IL, USA). Continuous variables were expressed as means ± standard deviations or ranges, and categorical

variables were expressed as frequencies or percentages. Student’s t test was used to compare continuous

variables, and Chi-squared test and Fisher’s exact test were used to compare categorical data. The

Kaplan–Meier method was applied for the analysis of disease-free survival (DFS) and overall survival (OS).

Cox proportional hazards analysis was performed to estimate prognostic factors for DFS in the total

population. A p-value <0.05 was considered to be statistically significant.

Results

General characteristics of patients

Sixty-one patients were enrolled in this study. The clinical characteristics of the patients in the two groups

are listed in Table 1. No significant differences were found between the groups in the preoperative clinical

parameters, including age, sex, body mass index (BMI), American Society of Anesthesiologists (ASA)

Classification, and preoperative CA 19-9.

Perioperative outcomes

The perioperative outcomes are summarized in Table 2. Notably, no statistically significant differences

were found regarding the operation time, intraoperative transfusion, pancreas texture, pancreas duct size,

postoperative hospital stay, and postoperative complications, such as postoperative pancreatic fistula,

delayed gastric emptying (DGE), and postpancreatectomy hemorrhage (PPH). However, the mean

estimated blood loss was significantly lower in the LPD group (232.59±178.68 mL) than in the OPD group

(448.82±343.83 mL; p<0.003).

Short-term oncologic outcomes

Table 3 shows the pathologic characteristics. The LPD groups showed comparable short-term oncologic

outcomes to those of OPD. No significant difference was found in the tumor size, number of retrieved LNs,

number of metastatic LNs, T-stage, N-stage(AJCC8th), tumor grade, R-status, lymphovascular invasion,

and perineural invasion (PNI).

Long-term oncologic outcomes

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In univariate analysis, the recurrence rate was higher in the OPD group than in the LPD group (67.65 vs

25.93%; p=0.002; Table 2). In subsequent multivariable logistic regression analysis, recurrence was found

to be associated with the laparoscopic approach [odds ratio (OR)=0.06; 95% confidence interval (CI): 0.01-

0.3732; p=0.002] and pathologic N 1/2 stage (N1: OR=7.39, 95% CI: 1.34-40.60, p=0.021; N2: OR=82.44,

95% CI, 2.31-2931.26) (Table 4). During the follow-up period in the LPD and OPD groups (median: 16.0

months in the LPD group vs 21.5 months in the OPD group), no significant difference was found in the

overall survival between the two groups (44.62 vs 45.29 months, respectively; p=0.223; Fig. 2a). However,

DFS was better in the LPD group than in the OPD group (34.19 vs 23.27 months; p=0.027; Fig. 2b). In the

univariate Cox proportional hazard model, significant predictors of DFS included pathologic N1 stage

[hazard ratio (HR)=4.90; 95% CI: 1.99-12.06; p=0.001], pathologic N2 stage (HR=5.78; 95% CI: 1.75-

19.12; p=0.004), positive lymph node ratio (LNR) (HR=1.05; 95% CI: 1.01–1.08; p=0.002), patient age

(HR=0.95; 95% CI: 0.91-0.99; p=0.017), R status (HR=2.46; 95% CI: 1.13-5.36; p=0.02) and

lymphovascular invasion (LVI) (HR=6.74; 95% CI: 2.82-16.11; p<0.001). In the multivariate Cox

proportional model with backward stepwise selection, only LVI (HR=6.74; 95% CI, 2.82-16.11; p<0.001)

remained significant predictors of survival (Table 5). The surgical approach, whether LPD or OPD, was not

found to be an independent prognostic factor in predicting long-term oncologic outcomes.

Comparison of the postoperative time-dependent inflammatory scores and WBC count

Regarding the linear mixed model, no significant difference was found in the change in the inflammatory

scores (LMR, NLR, PLR) over time between the groups. In the same analysis, no significant difference was

found in the differentiated WBC count according to the time between the groups (Fig. 3).

Discussion

Laparoscopic distal pancreatectomy is considered an effective modality to manage resectable cancer in

the pancreatic body and tail. [19] We also reported that the minimally invasive surgical technique for well-

selected left-sided pancreatic cancers provides technical feasibility and oncologic safety. [20] Moreover,

preoperatively determined Yonsei Criteria can predict excellent long-term oncologic outcomes. [21] Some

reports have investigated the oncologic safety of LPD for pancreatic head cancer; however, no common

opinion has yet been established.

With continuous effort to improve the techniques for minimally invasive PD and educational programs,

LPD has been performed by many surgeons in selected centers. [4,7,17,22] The feasibility and safety of

LPD have been studied, and advantages, such as lower blood loss, shorter hospital stay, more R0

resections, and fewer DGE, have been reported repeatedly. [5,23] However, according to a recent report

on the meta-analysis of three randomized control trials (RCTs), LPD showed no advantage over OPD at

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the current level of evidence. [24] The learning curve of LPD is long, and the advantage of LPD is unclear

due to difficulty in the reconstruction phase. Nevertheless, research on the feasibility and survival has

persisted. [22]

The LNR, lymphovascular invasion (LVI), margin-negative resection rate, and postoperative complications

are relative factors affecting the long-term oncologic outcome in pancreatic cancer patients. Regarding the

recent literature, it is difficult to explain that LPD is better than OPD in the operative outcome alone

concerning the oncologic outcome. [7,25,26] Kendrick et al. reported that margin-negative resection was

not different between the LPD and OPD groups. [7] In the multivariable analysis of this study, LVI was

found to be the only independent factor affecting DFS.

The oncologic outcome for minimally invasive PD is not conclusive. Some reports have demonstrated that

LPD has a positive effect on the long-term oncologic outcome as well as short-term operative outcome in

patients with pancreatic head cancer. Kendrick et al. reported that LPD is superior regarding the

progressive-free survival as well as short-term operative outcome [7] because it provides advantages such

as a shorter hospital stay and quicker recovery, allowing patients to recover in a timely manner and pursue

adjuvant chemotherapy based on the ESPAC-3 trial in which the time to adjuvant chemotherapy was less

than 12 weeks in the LPD group, affecting the oncologic outcome. In addition, a recent meta-analysis of PD

in PC patients reported that LPD is associated with longer DFS than OPD. [8] This study has suggested

that DFS is better in the LPD group. However, no significant difference was found in the time period to

adjuvant chemotherapy between the groups.

In this study, recurrence shows a significant difference between the two groups. Although there is no

statistically significant difference in pathologic characteristics between the two groups, more advanced

disease (T3 and N1 or N2) appears to be included in the OPD group. And It could be a reason for the

difference in recurrence. Another possibility is that there is a significant difference length of follow-up

between the two groups (LPD vs. OPD 17.25 ± 11.00 vs. 25.35 ± 15.77, p = 0.022), which may also affect

the recurrence rate.

The advantages of minimally invasive PD, such as less trauma, reduced pain, and faster recovery, are no

longer debatable. Minimally invasive surgery has become the standard of care in various surgical

procedures, such as gastrectomy [27] and colectomy [28]. However, studies concerning the mechanism of

the physiologic and immunologic effects of minimally invasive surgery on survival remains insufficient. As

part of such efforts, an increased systematic inflammatory response, as reflected by inflammatory markers

such as interleukin-6 (IL-6) and C-reactive protein, is related to postoperative complications. Based on the

properties of minimal invasive surgery that reduces the inflammatory response, comparison of the

inflammatory markers between LPD and OPD revealed a meaningful difference in various surgical

procedures. [29,30] Instead of inflammatory markers, inflammation-based scores, such as the NLR, PLR,

LMR, modified GPS, and PNI, have been proposed as prognostic factors for several cancers. [13-15] In this

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study, no significant difference was found in the inflammatory score and WBC count between the LPD and

OPD groups according to the time course immediately after surgery.

In the present study, in order to enhance the technical and oncologic feasibility of LPD, we performed an

only per-protocol based comparative analysis between OPD and LPD in treating PDAC. When analyzing

intention-to-treat analysis (including 2 cases with intraoperative conversion to OPD), it also found that LPD

was not inferior to OPD in treating PDAC (Supplements), suggesting LPD can be an appropriate alternative

option in managing well-selected resectable pancreatic cancer.

This study possessed several limitations. It is a single-center retrospective study, based on a small

sample size, the potential for undetected selection bias and the length of follow-up. Therefore, further

studies to explain the potential oncologic benefit of LPD for pancreatic cancer need to be performed based

on a larger study population and sufficient long-term follow-up data.

In conclusion, LPD is not only feasible and safe in patients with pancreatic head cancer but also provides

a benefit such as a short-term operative outcome and long-term oncologic outcome. In the future, it will be

necessary to verify the long-term oncologic outcome through large-scale RCTs and identify the related

mechanisms.

Acknowledgments

Author Contributions

Munseok Choi acquired and analyzed the data and drafted the manuscript. Ho Kyoung Hwang and Seoung

Yoon Rho revised the manuscript. Woo Jung Lee revised the manuscript. Chang Moo Kang conceived and

designed the study, revised, and gave final approval to the manuscript.

This manuscript was presented at the 31st Meeting of the Japanese Society of Hepato-Biliary-Pancreatic

Surgery.

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Figure 1. Study flow diagram

Figure 2. Kaplan-Meier survival curves representing disease free survival and overall survival for

pancreaticoduodenectomy in total population (n=61).

Figure 3. Comparing inflammatory scores and the WBC count

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Table 1. Patient Characteristics

LPD (n=27) OPD (n=34) p value

Male / Female 12(44.44) / 15(55.56) 18(52.94) / 16(47.06) 0.609

Age 63.35 ± 9.48 63.35 ± 9.48 0.708

BMI 23.2 ± 2.12 22.94 ± 3.46 0.726

ASA classification 1.000

1 2(7.41) 2(5.88)

2 12(44.44) 16(47.06)

3 13(48.15) 16(47.06)

CA 19-9 242.44 ± 521.77 309.83 ± 471.42 0.599

BMI indicates body mass index, ASA, American Society of Anesthesiologists

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Table 2. Perioperative outcomes


Operation time 477.7 ± 60.75 471.21 ± 78.62 0.725

EBL 232.59 ± 178.68 448.82 ± 343.83 0.003

Intraoperative transfusion 0(0.00) 2(5.88) 0.498

Pancreas Texture 0.371

Soft 13(48.15) 9(29.03)

Intermediate 1(3.70) 2(6.45)

Hard 13(48.15) 20(64.52)

Pancreas duct size 4.44 ± 2.46 4.09 ± 2.4 0.578

POPF 0.700

None 17(62.96) 24(70.59)

BL 8(29.63) 6(17.65)

B 1(3.70) 3(8.82)

C 1(3.70) 1(2.94)

DGE 0.422

None 23(85.19) 30(88.24)

A 3(11.11) 2(5.88)

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B 0(0.00) 2(5.88)

C 1(3.70) 0(0.00)

PPH 0(0.00) 1(2.94) 1.000

Recurrence 7(25.93) 23(67.65) 0.002

Adjuvant chemotherapy 21(77.78) 27(79.41) 1.000

Period to chemotherapy 59.52 ± 32.14 55.15 ± 20.39 0.568

Hospital stay 21.19 ± 11.13 19.94 ± 9.79 0.928

EBL indicates estimated blood loss, POPF, postoperative pancreatic fistula, DGE, delayed

gastric emptying, PPH, postoperative hemorrhage

Table 3. Pathologic characteristics


Tumor size 2.89 ± 1.00 2.99 ± 1.38 0.761

T stage 0.601

1 6(22.22) 7(20.59)

2 17(62.96) 18(52.94)

3 4(14.81) 9(26.47)

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N stage 0.721

0 14(51.85) 14(41.18)

1 10(37.04) 16(47.06)

2 3(11.11) 4(11.76)

Retrieved LN 13.33 ± 9.21 20.65 ± 9.47

Positive LN 1.11 ± 1.87 1.32 ± 1.59

LNR 6.89 ± 10.99 6.41 ± 8.47

LVI 0.117

0 18(69.23) 16(47.06)

1 8(30.77) 18(52.94)

PNI 0.742

0 4(15.38) 7(20.59)

1 22(84.62) 27(79.41)

Histologic type 0.589

Well 2(9.09) 7(20.59)

Moderate 16(72.73) 22(64.71)

Poor 2(9.09) 4(11.76)

Undifferentiated 0(0.00) 0(0.00)

Adenosquamous 1(4.55) 1(2.94)

Mucinous 1(4.55) 0(0.00)

R status 0.092

0 25(92.59) 24(70.59)

1 2(7.41) 9(26.47)

2 0(0.00) 1(2.94)

LN indicates lymph node, LNR, positive lymph node ratio, LVI, lymphovascular invasion, PNI,

perineural invasion

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Table 4. Multivariable logistic regression analysis of recurrence risk factors

B S.E. Wald P-value Odds ratio 95% CI

LPD -2.797 0.923 9.175 0.002 0.061 0.01-0.373

N stage

N0 7.818 0.02

N1 2.001 0.869 5.307 0.021 7.398 1.348-40.603

N2 4.412 1.822 5.864 0.015 82.444 2.319-2931.263

LPD indicates laparoscopic pancreaticoduodenectomy

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Table 5. Cox proportional hazards regression model for Disease free survival

Variables Univariable analysis Multivariable analysis

HR 95% CI p-value HR 95% CI p-value

Sex 1.005 0.514-2.165 0.883

Age 0.953 0.915-0.991 0.017

BMI 0.910 0.790-1.048 0.190

ASA

1 0.267

2 0.811 0.186-3.536 0.781

3 0.445 0.097-2.049 0.299

CA 19-9 1.000 1.000-1.001 0.166

Operating time 1.003 0.998-1.008 0.223

EBL 1.001 1.000-1.001 0.274

LNR 1.051 1.019-1.085 0.002

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T stage

1 0.363

2 1.601 0.599-4.277 0.348

3 0.858 0.248-2.972 0.809

N stage

0 <0.001

1 4.909 1.998-12.060 0.001

2 5.785 1.750-19.122 0.004

Histologic grade

Well 0.606

Moderate 1.442 0.480-0.4334 0.515

Poor 2.987 0.715-12.478 0.134

Undifferentiated

Adenosquamous 2.732 0.287-25.993 0.382

Mucinous 0.000 0.000 0.979

LVI 6.744 2.822-16.115 <0.001 6.744 2.822-16.115 <0.001

PNI 1.507 0.567-4.007 0.411

R status

1&2 2.466 1.134-5.366 0.023

POPF grade > B 1.502 0.452-4.993 0.507

Period to

chemotherapy

0.997 0.979-1.015 0.724

BMI indicates body mass index, ASA, American Society of Anesthesiologists, EBL, estimated

blood loss, LNR, positive lymph node ratio, LVI, lymphovascular invasion, PNI, perineural

invasion, POPF, postoperative pancreatic fistula

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Figure 2. Kaplan-Meier survival curves representing disease free survival and overall survival for

pancreaticoduodenectomy in total population (n=61).

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Figure 3. Comparing inflammatory scores and the WBC count

comparing laparoscopic and open pancreaticoduodenectomy in ... · accepted article this article is...

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