Annals of Surgery

DOI: 10.1097/SLA.0000000000005132

The Impact of Neoadjuvant Treatment on Survival in Patients Undergoing

Pancreatoduodenectomy with Concomitant Portomesenteric Venous Resection: An
International Multicenter Analysis

Nikolaos Machairas, MD, PhD1*, Dimitri A Raptis, MD, MSc, PhD1, 25*, Patricia Sánchez
Velázquez, MD, FEBS, PhD2*, Alain Sauvanet, MD3, Alexandra Rueda de Leon, MD4,
Atsushi Oba, MD, PhD5, Bas Groot Koerkamp, MD, PhD6, Brendan Lovasik, MD23, Carlos
Chan, MD4, Charles Yeo, MD7, Claudio Bassi, MD, FACS, FRCS9, Cristina R Ferrone, MD8,
David Kooby, MD FACS23, David Moskal, BHSc7, Domenico Tamburrino, MD10, Dong-Sup
Yoon, MD, PhD22, Eduardo Barroso, MD11, Eduardo de Santibañes, MD, PhD12, Emanuele F
Kauffmann, MD13, Emmanuel Vigia, MD11, Fabien Robin, MD, MSc14, Fabio Casciani, MD9,
Fernando Burdío, MD, PhD2, Giulio Belfiori, MD10, Giuseppe Malleo, MD, PhD9, Harish
Lavu, MD7, Hermien Hartog, MD, PhD6, Ho-Kyoung Hwang, MD, PhD22, Ho-Seong Han,
MD, PhD15, Hugo P. Marques MD, PhD11, Ignasi Poves, MD, PhD2, Ismael Domínguez
Rosado, MD4, Joon-Seong Park, MD, PhD22, Keith D Lillemoe, MD8, Keith Roberts, MD,
PhD17, Laurent Sulpice, MD, PhD14, Marc G Besselink, MD, PhD19, Mahmoud Abuawwad,
MD20, Marco Del Chiaro, MD5, Martin de Santibañes, MD, PhD12, Massimo Falconi, MD10,
Mizelle D'Silva, MD15, Michael Silva, MBBS, MS, MD, FRCS16, Mohammed Abu Hilal,
MD, PhD, FRCS, FACS20, 24, Motaz Qadan, MD, PhD8, Naomi M Sell, MD8, Nassiba
Beghdadi, MD3, Niccolò Napoli, MD13, Olivier RC Busch MD, PhD,19 Oscar Mazza, MD12,
Paolo Muiesan, MD, FRCS, FEBS17, Philip C. Müller, MD21, Reena Ravikumar, MD16,
Richard Schulick, MD, MBA5, Sarah Powell-Brett, MBChB, MSc, MRCS17, Syed Hussain
Abbas, BM, BMedSci, MRCS16, Tara M Mackay, MD, PhD, MSc19 Thomas F Stoop, MD19,
Tom K Gallagher, MS, MCh, FEBS, FRCSI18, Ugo Boggi, MD, FEBS13, Casper van Eijck,
MD, PhD6, Pierre-Alain Clavien, MD, PhD21, Kevin C P Conlon, MA, MCh, MBA, FRCSI,
FACS18, Giuseppe Kito Fusai, MS FRCS1, 25

1 Department of HPB Surgery and Liver Transplant, Royal Free Hospital NHS Foundation
Trust, London, UK

2 Department of Surgery, Parc de Salut Mar, Barcelona, Spain

3 Department of Surgery, Hôpital Beaujon, University of Paris, AP-HP, Clichy, France

4 Department of Pancreatic Surgery, National Institute of Medical Sciences and Nutrition,

Mexico City, Mexico

5 Division of Surgical Oncology, Department of Surgery, University of Colorado, Anschutz

Medical Campus, Colorado, CO, USA

Copyright © 2021 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
 6 Department of Surgery, Erasmus MC, University Medical Center Rotterdam, the
Netherlands

7 Department of Surgery, Thomas Jefferson University, Philadelphia, PA, USA

8 Department of Surgery, Massachusetts General Hospital, Boston, MA, USA

9 Department of Surgery, University Hospital of Verona, "Pancreas Institute," Verona, Italy

10 Department of Surgery, San Raffaele Hospital IRCCS, Vita-Salute University, Milano,

Italy

11 Department of Surgery, Curry Cabral Hospital, CHLC, Lisbon, Portugal

12 Department of Surgery, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina

13 Division of General and Transplant Surgery, University of Pisa, Pisa, Italy

14 Department of HPB and Digestive Surgery, Rennes University Hospital, Rennes, France

15 Department of Surgery, Seoul Naional University College of Medicine, Seoul National

University Bundang Hospital, Seoul, Korea

16 Department of HPB Surgery, Oxford University Hospitals NHS Foundation Trust, Oxford,
UK

17 Department of HPB Surgery and Liver Transplant, Queen Elizabeth Hospital,

Birmingham, UK

18 Department of HPB Surgery, St. Vincent’s University Hospital, Dublin, Ireland

19 Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, University of

Amsterdam, Amsterdam, the Netherlands.

20 Department of Surgery, University Hospital Southampton NHS Foundation Trust,

Southampton, UK

21 Department of Surgery and Transplantation, University Hospital Zurich, Zurich,

Switzerland.

22 Department of Surgery, Gangnam Severance Hospital, Yonsei University, Seoul, Korea

23 Department of Surgery, Emory Saint Joseph’s Hospital, Emory University, Atlanta, GA,
USA

24 Department of Surgery, Poliambulanza Foundation Hospital, Brescia, Italy.

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 25 Division of Surgery and Interventional Sciences, University College London, London,
UK.

* NM, DAR, and PSV shared first authorship.

Corresponding author:

Professor Giuseppe Kito Fusai, MS FRCS

Department of HPB Surgery and Liver Transplant

Royal Free London NHS Foundation Trust

Pond Street, London, NW3 2QG

Tel: +442077940500 Email: g.fusai@ucl.ac.uk

ABSTRACT

Objective: The aim of this study was to evaluate whether neoadjuvant therapy (NAT)
critically influenced microscopically complete resection (R0) rates and long-term outcomes
for patients with pancreatic ductal adenocarcinoma who underwent pancreatoduodenectomy
(PD) with portomesenteric vein resection (PVR) from a diverse, world-wide group of high-
volume centers.

Summary Background Data: Limited size studies suggest that NAT improves R0 rates and
overall survival compared to upfront surgery in resectable and borderline resectable
pancreatic cancer (R/BR-PDAC) patients.

Methods: This multicenter study analyzed consecutive patients with R/BR-PDAC who
underwent PD with PVR in 23 high-volume centers from 2009 to 2018.

Results: Data from 1192 patients with PD and PVR were collected and analyzed. The
median age was 68 [interquartile range (IQR) 60-73] years and 52% were males. Some 186
(15.6%) and 131 (10.9%) patients received neoadjuvant chemotherapy (NAC) alone and
neoadjuvant chemoradiotherapy (NACRT), respectively. The R0/R1/R2 rates were 57%,
39.3%, and 3.2% in patients who received NAT compared to 46.6%, 49.9%, and 3.5% in
patients who did not, respectively (p=0.004). The 1-, 3-, and 5-year OS in patients receiving
NAT was 79%, 41%, and 29%, while for those that did not it was 73%, 29%, and 18%,
respectively (p<0.001). Multivariable analysis showed no administration of NAT, high tumor
grade, lymphovascular invasion, R1/R2 resection, no adjuvant chemotherapy, occurrence of
Clavien-Dindo grade 3 or higher postoperative complications within 90 days, preoperative

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 diabetes mellitus, male sex and portal vein involvement were negative independent predictive
factors for OS.

Conclusion: Patients with PDAC of the pancreatic head expected to undergo venous
reconstruction should routinely be considered for NAT.

Key words: Resectable, Borderline resectable, Portomesenteric vein invasion, Pancreatic

Cancer, Neoadjuvant treatment, Chemotherapy, Radiotherapy, Pancreaticoduodenectomy,
Portal Vein Resection, Survival.

MINI-ABSTRACT

Limited size studies suggest NAT improves R0 rates and overall survival compared to
upfront surgery in resectable and borderline resectable pancreatic ductal adenocarcinooma
(R/BR-PDAC) patients. Our multicenter study confirmed the beneficial impact of NAT on
R/BR-PDAC patients undergoing pancreaticoduodenectomy with portomesenteric vein
resection in terms of complete resection and overall survival.

INTRODUCTION

Surgical resection with microscopically negative resection margins (R0) represents the
sole potentially curative treatment option for patients with pancreatic ductal adenocarcinoma
(PDAC).1 However, approximately only 15-20% of patients with PDAC of the pancreatic
head are eligible for resection at diagnosis whilst a proportion of patients will be diagnosed
with borderline resectable (BR) disease with their tumors exhibiting a variable degree of
involvement of the portomesenteric venous axis.2 Despite considered more technically
demanding than pancreatoduodenectomy (PD) alone, PD with synchronous portomesenteric
vein resections (PVR) and subsequent vascular reconstruction in patients with resectable and
BR-PDAC are regarded as equally safe and effective procedures in high-volume pancreatic
surgery units.3

Administration of multimodal neoadjuvant therapy (NAT) consisting of chemotherapy

(NAC) alone or chemotherapy combined with radiotherapy (NACRT) is increasingly
advocated in patients with BR-PDAC, who are at higher risk for microscopically incomplete
resections.4 A few small prospective trials have demonstrated that NAT in BR-PDAC
patients is safe, effective and well tolerated.5-7 NAT is not intended solely for downstaging,
thus facilitating radical (R0) resection, but also selects out patients with progressive or
disseminated tumors, potentially sparing these patients unnecessary complex surgery.8
Furthermore, given the high rates of PD-related morbidity and declining postoperative

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 clinical status, a significant percentage of patients are hindered from the administration of
adjuvant therapy; hence NAT could be considered a useful tool, administering the maximum
potential load of chemotherapy and allowing for enhanced locoregional and systemic control
of disease.3, 8, 9

Limited cohort size studies have shown that NAT is associated with superior survival in
patients with resectable (R)/BR-PDAC compared to those undergoing upfront surgery,
despite lower overall resection rates.10, 11 Whether NAT improves outcomes specifically in
patients undergoing PD with PVR remains poorly investigated with only a few studies with
limited number of patients published.12, 13 These reports have suggested that NAT prior to PD
with PVR was associated with increased R0 rates and improved survival compared to patients
undergoing immediate surgery.12 These results however have not been confirmed with large
enough cohorts of patients to provide a robust, statistically significant validation.

The aim of this international multicenter study was to investigate the impact of NAT on
R0 rates and long-term oncological outcomes in patients with R/BR-PDAC, who underwent
PD with concurrent PVR in a large cohort managed in high-volume pancreatic surgery
centers, enough to provide a more robust support.

METHODS

Study design

This was a retrospective, single cohort, multicenter, international, study assessing the
impact of NAT on long-term oncological outcomes in patients with R/BR-PDAC undergoing
PD with PVR. The initial cohort was derived from a different study aiming at establishing
benchmarks after PD with PVR for any type of indication (NCT04053998)3. This study was
approved as an international audit by the data custodian of the Royal Free Hospital London,
UK. It was conducted in accord with the ethical standards of the Helsinki Declaration of
1975. This study is compliant with the STROBE recommendations for reporting cohort
studies.14

Setting

Twenty-three high-volume centers from Asia, Europe, and America, which maintained
a prospective patient database including long-term outcomes, were included. Data collection
took place from August 2019 until January 2020. Patient recruitment included the 10-year
period from January 2009 to December 2018.

Data were collected through a specially designed, secure, password protected, and
encrypted online data entry management system (DEMS) (WhippleBenchmarks.org), as
previously described.15 This platform met international standards for online databases
including fully anonymized data.

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 Participants

Only patients with PDAC undergoing open PD with PVR were included in this study.
Patients <18 years of age, laparoscopic or robotic approaches, arterial resection and
reconstruction, and distal or total pancreatectomy with PVR were excluded. Patients were
required to have at least two years of postoperative follow up, unless they died within this
period.

Variables and outcome measures

The overall patient, neoadjuvant therapy (chemotherapy or chemoradiotherapy),

diagnosis, operation, histopathology characteristics, complication grading according to
Clavien Dindo classification and the comprehensive complication index® as well as long-
term oncological outcomes are reported for descriptive purposes.16, 17 Short-term oncological
outcomes included the resection margin status that was uniformly reported (R0: indicating
≥1 mm margin; R1: <1 mm clearance; R2: macroscopic residual tumor). The circumferential
resection margin (CRM) was also standardized and uniformly reported.18 Long-term
oncological outcomes included the overall survival (OS). The calculated OS referred only to
patients who finally underwent resection, whilst patients who received NAT and did not
qualify for surgery were not included in this study.

Bias

The primary investigators made all efforts to address and minimize any potential
sources of bias related to such large-scale retrospective multicenter international studies as
reported in the supplementary methods, http://links.lww.com/SLA/D338.

Study size

The study size was defined after including patients that underwent PD with PVR for
PDAC only. In order to perform a meaningful analysis with an adequate event rate, the
patient recruitment period spanned 10 years, as this particular procedure is less commonly
performed. The authors did not perform a post-hoc power calculation, as the sample size was
relatively large.

Statistical methods

Statistical analysis was performed using R (Supplementary methods,

http://links.lww.com/SLA/D338)

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 RESULTS

Participants

A total of 1192 patients who underwent PD with PVR in 23 centers were included in
our analysis. The variability of NAT administration among centers is shown in Figure 1A.
The percentage of NAT administered per year during the inclusion period is shown in Figure
1B. The median age was 68 (IQR 60-73) years and 620 (52%) were male. 317 (26.5%)
received NAT prior to PD with PVR. More specifically some 186 (15.6%) and 131 (10.9%)
patients received NAC alone and NACRT, respectively. Patient and operative details are
shown in Table 1.

Perioperative outcomes

Postoperative outcomes are shown in Table 2. Comprehensive complication index

®
(CCI ) scores were similar among the 2 groups at discharge, however, postoperative
pancreatic fistula rates were significantly lower in the NAT group compared to the no NAT
group (7.6 % vs 15.1%, p<0.001). Hospital length of stay and in hospital mortality was
similar between the two groups.

Patients who received NAT had smaller size resected tumors [2.7 (IQR 2-3.5) vs. 3.0
(2.5-3.8) cm, p<0.001], lower rates of N1/N2 disease [(57%) vs (81.4%), p<0.001)] as well as
lower rates of lymphovascular [(58.1%) vs. (74%), OR 0.49 (95% CI 0.37-0.65), p<0.001]
and perineural invasion [(77.1%) vs. (88.6%), OR 0.43 (95% CI 0.31-0.62, p<0.001]
compared to the upfront surgery group. Patients receiving NAT also had lower rates of PV
involvement on final histology [(31.5%) vs. (49.3%), p<0.001]. The R0/R1/R2 rates were
57.5%, 39.3%, and 3.2% in patients who received NAT compared to 46.6%, 49.9%, and
3.5% in patients who did not, respectively (p=0.004)(Table 2).

Long-term oncologic outcomes

During a median follow up period of 34 months (IQR 16-55) the median OS of the
whole cohort was 29 months. The median OS for the NAT vs. no NAT groups was 28 (95%
CI 25-34) vs. 21 (95% CI 19-23) months (p<0.001), respectively. The 1-, 2-, 3-, and 5-year
OS in patients that received NAT was 79%, 57%, 41%, and 29%, while for those that did not
it was 74%, 44%, 30%, and 18%, respectively [HR 0.72 (95%CI 0.60-0.86), p<0.001](Figure
2A). More specifically, the 1-, 2-, 3-, and 5-year OS in patients that received NACRT were
80%, 60%, 46% and 36%, while it for patients who received NAC alone were 78%, 56%,
37% and 22%, respectively (p=0.001) (Figure 2B).

Multivariable analysis

On multivariable Cox-regression analysis, 10 independent prognostic factors were

identified. No administration of NAT [HR 2.29 (1.21-4.35) p=0.011], R1 and R2 resection

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 [HR 1.88 (1.05-3.38) p=0.034 and HR 1.71 (1.26-2.33) p=0.001], no adjuvant chemotherapy
[HR 1.88 (1.34-2.65) p<0.001], high tumor grade [HR 1.83 (1.09-3.09) p=0.023], occurrence
of Clavien Dindo grade 3 or higher postoperative complications within 90 days [HR 1.55
(1.10-2.18) p=0.013], lymphovascular invasion [HR 1.39 (0.96-2.01) p=0.083], preoperative
diabetes mellitus [HR 1.35 (1.01-1.80) p=0.041], male sex [HR 1.28 (0.97-1.69) p=0.086]
and portal vein involvement on histology [HR 1.28 (1.96-1.71) p=0.091] were independently
associated with worse survival (Figure 3).

DISCUSSION

This study evaluated the largest series of patients with pancreatic ductal
adenocarcinoma (PDAC) undergoing pancreatoduodenectomy (PD) with portomesenteric
vein resection (PVR) to date. We demonstrated that patients who received preoperative
treatment and ultimately underwent resection were more likely to successfully undergo R0
resection, which in turn translated into superior survival compared to patients who underwent
immediate surgery. Our study more specifically highlighted that administration of
neoadjuvant chemoradiotherapy (NACRT) was associated with improved survival rates
compared to neoadjuvant chemotherapy (NAC) alone or upfront surgery.

Our results illustrate a variable yet increasing use of neoadjuvant therapy (NAT) among
centers, which has shifted over time based on emerging evidence. Current international
recommendations for administration of NAT in borderline resectable (BR) PDAC derive
from only a few well-designed RCTs and mainly from systematic reviews of patient cohorts
not reaching high levels of evidence.19-21 The European Society of Medical Oncology
(ESMO) guidelines recommend a period of chemotherapy (gemcitabine or FOLFIRINOX)
followed by chemoradiation prior to surgical resection in patients with BR-PDAC not
enrolled in a clinical trial.22 The latest National Comprehensive Cancer Network (NCCN)
guidelines advise that BR-PDAC patients who are at high risk for positive surgical margins
are not considered suitable candidates for upfront resection but instead may benefit from
NAT.4 The proposed regimens include FOLFIRINOX, modified FOLFIRINOX or
gemcitabine plus albumin-bound Paclitaxel followed by CRT. Lastly, the American Society
of Clinical Oncology (ASCO) clinical practice guidelines similarly recommend NAT for
patients with high-risk features including a close proximity or direct involvement of
portomesenteric vasculature on cross-sectional imaging that does not meet appropriate
criteria for primary resection.23

In this study patients receiving NAT were observed to have relatively smaller tumors,
possibly as a result of downstaging, and higher rates of R0 resection than those undergoing
immediate surgery. Regardless of the administered chemotherapeutic regimen and
sequencing with or concurrent radiation therapy, our results are in line with the outcomes of
previously reported smaller size retrospective and prospective phase II studies.19 In a French
National retrospective study, Delpero et al. investigated the impact of NAT on survival of
BR-PDAC patients who underwent concomitant PVR.12 The authors, similarly to our study,
showed that patients receiving NAT were more likely to undergo a negative margin resection

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 compared to those undergoing upfront surgery (71% vs. 57%), while administration of NAT
was independently associated with improved survival on multivariate analysis.12 The
ALLIANCE A021101 trial recruited BR-PDAC patients who received NACRT, of whom
68% eventually underwent resection, with 73% requiring concomitant PVR and
reconstruction.5 The authors reported a 93% R0 rate. A similarly high R0 rate of 97% was
also more recently reported by Murphy et al. following administration of NACRT in BR-
PDAC patients.7 Versteijne et al. meta-analyzed 38 studies reporting outcomes for upfront
surgery vs. NAT for both resectable and BR-PDAC; in a subgroup analysis of studies
comprising BR-PDAC patients who received NAT and underwent resection, the R0 rate was
89%, higher than the upfront surgery BR-PDAC group (64%).10

Our study demonstrated a clear survival benefit in patients receiving NAT who
eventually underwent resection compared to those undergoing immediate PD with PVR. This
is also in agreement with the outcomes of two up-to-date meta-analyses.24 Giovinazzo et al.
demonstrated a significant survival benefit in favor of gemcitabine-based NAT over upfront
surgery in BR-PDAC patients.24 The median OS of patients in the NAT group was 28 months
compared to 13 months in patients undergoing immediate surgery. In another meta-analysis
of RCTs comprising both resectable and BR-PDAC patients randomized towards upfront
surgery or NAT, Cloyd et al. similarly showed improved OS in NAT groups with a median
survival of 25 compared to 19 months in the immediate surgery groups.25 Furthermore,
despite being associated with greater toxicities than gemcitabine, FOLFIRINOX and its
modified combination are also regarded as a highly effective NAT regimen shown to improve
survival compared to upfront surgery in BR-PDAC.5, 11, 26 The outcomes of the much awaited
ESPAC 5F trial most robustly confirmed these results showing that NAT improves OS in
BR-PDAC patients who subsequently undergo resection.20

Whether NAC alone or NACRT has a larger impact on OS in resected BR-PDAC

patients remains controversial. Despite the fact that radiotherapy has a convincingly
significant role in establishing local control and reduction of local recurrence when used in
the preoperative setting, its practical impact on long-term outcomes remains unclear with
conflicting outcomes published.11, 27-29 In their meta-analysis Versteijne et al. failed to show
significant difference in OS among patients who received NAC and NACRT.10 Nevertheless
this outcome should be interpreted with caution given the significant heterogeneity among the
included studies with regards to radiation doses and NAT sequencing as well as inclusion of
studies with resectable PDAC patients. Our study showed NACRT was superior to NAC in
terms of OS rates, confirming the potentially synergistic action between chemo and
radiotherapy observed in a recent trial.21

A complicated postoperative course after resectional surgery for pancreatic cancer is

known to affect negatively OS, partly explained, as patients frequently cannot receive
adjuvant treatment in a timely fashion.30 Our results conform well with this evidence as both
serious complications and no adjuvant chemotherapy were found to be associated with poorer
survival in the multivariable analysis model. Patients with preoperative diabetes mellitus
(DM) were also identified to independently have a worse survival. This negative prognostic

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 effect has been previously shown in multiple prospective and retrospective studies
comprising mostly resectable PDAC patients.31, 32 While some studies have demonstrated that
hypersecretion of insulin, in the context of insulin resistance, is linked with enhanced
angiogenesis and invasion as well as a reduced apoptotic effect on pancreatic tumor cells,
others have suggested that further, not yet elucidated cellular processes may also be held
responsible for the poor prognosis associated with DM.31, 33

A number of inherent limitations to this study should be addressed. Initially the

retrospective nature bears the challenges of data collection as well as a difference in follow
up methods. Nevertheless, all included centers had to have a maintained prospective database
of their patients enclosing short- and long-term outcomes in order to be included in our study.
Our study could not elucidate which patients were chosen to receive NAT given the
variations in standard of care among participating centers. The proportion of patients and the
regimens used in the NAT group varied among centers, which is the inevitable consequence
of variations in national and international recommendations and change of protocols over the
inclusion period. This limitation is only partially compensated by the awareness that most
patients were treated with FOLFIRINOX or gemcitabine based chemotherapy in the NAC
group, whereas both sequential chemotherapy followed by radiation treatment and
chemoradiotherapy with low dose of chemotherapeutic drug as a radiosensitizer were used in
the NACRT group. Another limitation is the lack of the denominator, the exact number of
patients who were initiated on NAT but ultimately did not qualify for resection due to poor
performance status or local/distant disease progression.34 As shown by prospective studies,
approximately 20-30% of patients who receive NAT do not finally qualify for surgical
exploration due to disease progression or poor performance status.19 Hence our group of NAT
patients who finally underwent PD with PVR possibly represents a selected group of patients
with favorable clinical, oncological and potentially biologic tumor characteristics. Moreover,
whether patients chosen to receive NAT who became unresectable after NAT could have
been primarily resected and survived remains equivocal. Capturing the dropout rate
specifically in retrospective studies is very challenging and was beyond the scope of our
study, as we did not aim to perform an intent-to-treat analysis. Lastly our analysis did not
take under consideration tumor biology, which has partly been shown to impact long-term
prognosis.

To conclude, our study confirmed the beneficial impact of NAT in the largest, to date,
series of R/BR-PDAC patients, who underwent PD with PVR in terms of complete resection
and OS. While the optimal chemotherapeutic regimens as well as the benefit of additional
preoperative radiation therapy remain to be accurately determined by high quality RCTs, our
outcomes support the routine administration of NAT in patients expected to require
portomesenteric vein resection during pancreatoduodenectomy.

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 OTHER INFORMATION

Funding

The development and maintenance of the Data Entry Management System (DEMS)
was supported by the Fiorina Royal Free Charity. The Fiorina Royal Free Charity Members
had no influence on the study design, the analysis or interpretation of the results of this study.

Conflict of interest

The authors have no conflict of interest to declare.

DISCUSSANTS

Jakob R. Izbicki (Hamburg, Germany)

I would like to thank the ESA for the privilege of being the first discussant of this paper, and
the authors for this interesting study. The present work evaluates the effect of neoadjuvant
treatment (NAT) in patients receiving a pancreaticoduodenectomy with concomitant
portomesenteric venous resection in a retrospective multicenter study. The main conclusion is
that NAT provides a higher rate of margin negative resections (R0) and a better long-term
survival rate in this patient subgroup. The authors suggest that patients with borderline
resectable pancreatic ductal adenocarcinoma (BR-PDAC) should be routinely considered for
neoadjuvant treatment. The presented study is based on more than 20 centers, spread over
three continents, and spanning a time period of nearly ten years.

One primary outcome of the present study is an improved R0 resection rate. The study cohort
originates from various countries and the pathology work-up does differ between the centers
and over time. The authors are aware of that fact, and it is understandable that a pragmatic
approach was chosen.

However, looking at the margin resection status, the significant result comparing R0 vs. R1 is
only based on the dorsal resection margin.

My first question is as follows: how do the authors explain the missing significance of the
medial resection margin, especially towards the vessels? One would expect that the resection
margin towards the SMV and SMA to be significantly different between the groups, and not
only the dorsal resection margin. As such, to what extent was it possible to retrospectively
report the RM status based on the current standards of the Royal College of Pathologists?

In the end, I have to ask whether all centers stuck to the CRM classification, including the
inking of all dissection and resection margins over the whole study period (≤1mm). If not,
was the tumor clearance (at possibly non-inked margins) recorded, and if so, how?

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 Second, the baseline limitation of the missing standards regarding the margin assessment and
definition is causing major concerns about the possibility and quality of retrospective margin
assessments.

The authors chose to include patients with venous resections and use the venous resection as
a surrogate for borderline assessment. Unfortunately, this is not the definition of borderline
resectable cancers. Tangential as well as segmental venous resections are sometimes
necessary, although portal vein involvement is less than 180°. In addition, arterial
involvement was not considered at all.

Therefore, the question arises as to whether resectable tumors per definition were also
included in the study cohort. Having this limitation in mind, do the authors think that the
interpretation of the study cohort as borderline resectable is justified?

Third, the authors decided to include stage IV patients as well as R2 resected patients. These
types of patients are palliative ones. If these patients do not overlap, the study includes up to
65 patients with palliative resections. As I have mentioned at the beginning, the study needs
to avoid any unnecessary confounding effects. Therefore, my question is: why did the authors
decide not to exclude these patients? Although the authors are providing details on
neoadjuvant and adjuvant therapy, the median number of cycles given to the patients is
missing. Do the authors believe that the impact of NAT and AT can be properly assessed, if
we don´t know how many patients received the full course of treatment?

My last question relates to the multivariate analysis. Were all variables included in the
multivariate analysis significant within the univariate analysis? Why did the authors choose
to keep non-significant variables in the multivariate analysis, and in general, why did the
authors only include “no neoadjuvant radiochemotherapy” and not “no neoadjuvant therapy”,
since the conclusion of the study is that NAT should be considered in BR-PDAC patients?

Response From Giuseppe K Fusai (London, United Kingdom)

Thank you, Dr. Izbicki, for the extensive review, discussion and questions. First, with regards
to the resection margin status, I would agree that the classifications of the definition of R1
resection varies across different countries and continents. As you say in your review, we had
to adopt a pragmatic approach, since this was a retrospective study. We used a case reporting
form based on that provided by the Royal College of Pathologists. With a specific reference
to the medial margin, you’re absolutely right when you say that the portal vein groove is
clearly defined by the indentation of the pancreatic head, whereas the dorsal margin is less
defined, as the indentation of the superior mesenteric artery merges with the posterior margin
itself.

Regarding your second question, this is probably one of the limitations of any retrospective
study on borderline resectable disease. The fact that patients require some form of venous
resection is somehow a validation of the definition of borderline resectable disease. Several

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 studies on borderline resectable disease are based on intraoperative findings. However, I
entirely accept that the definition of borderline resectable disease is based on a radiological
classification.

With regards to your third question, we did not exclude patients with R2 resections, as this
was a histopathological finding, or actually, a surgical finding at the time of surgery.
However, I would agree that patients with R2 resections should be considered palliative.
Also, I think that the number of patients, if any, with metastatic disease was very low.

Regarding your final question, I agree that the lack of complete information on neoadjuvant
treatment is a limitation. We initially aimed to capture the entire number of cycles and type of
chemotherapy regime used. For practical reasons, we didn’t go into the detail, but this is
definitely something we should look into. It’s a very valid criticism.

Antonio Pinna (Weston, USA)

Is the difference in tumor diameter supposed to be a result of the NAT, or are you afraid of a
possible selection bias?

Response From Giuseppe K Fusai (London, United Kingdom)

Thank you for your very valid remark. It is possible that there might be a selection bias, but
undoubtedly, many crucial histopathological parameters were better in the NAT group, which
is why I referred to the possibility of a biological switch.

Christian Toso (Geneva, Switzerland)

Thank you for your nice study. Can you please comment on the risk of not reaching surgery
after neo-adjuvant chemotherapy (drop-out)? Is the superiority of neoadjuvant chemotherapy
maintained, even when looking at survival from the time of diagnosis?

Response From Giuseppe K Fusai (London, United Kingdom)

We do not have the denominator. While we did not intend to carry out an “intention to treat”
analysis, it is important information, which is very difficult to capture in retrospective
multicenter studies. Recent prospective and randomized controlled studies have reported a
drop-out rate of approximately 20%. In my view, this potential risk is justified by the clear
benefit of overall survival for those patients who are ultimately resected following
neoadjuvant treatment.

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 REFERENCES

1. Grossberg AJ, Chu LC, Deig CR, et al. Multidisciplinary standards of care and recent
progress in pancreatic ductal adenocarcinoma. CA Cancer J Clin 2020; 70(5):375-
403.

2. Bockhorn M, Uzunoglu FG, Adham M, et al. Borderline resectable pancreatic cancer:

a consensus statement by the International Study Group of Pancreatic Surgery
(ISGPS). Surgery 2014; 155(6):977-88.

3. Raptis DA, Sanchez-Velazquez P, Machairas N, et al. Defining Benchmark Outcomes

for Pancreatoduodenectomy With Portomesenteric Venous Resection. Ann Surg 2020;
272(5):731-737.

4. Tempero MA, Malafa MP, Chiorean EG, et al. Pancreatic Adenocarcinoma, Version
1.2019. J Natl Compr Canc Netw 2019; 17(3):202-210.

5. Katz MH, Shi Q, Ahmad SA, et al. Preoperative Modified FOLFIRINOX Treatment
Followed by Capecitabine-Based Chemoradiation for Borderline Resectable
Pancreatic Cancer: Alliance for Clinical Trials in Oncology Trial A021101. JAMA
Surg 2016; 151(8):e161137.

6. Jang JY, Han Y, Lee H, et al. Oncological Benefits of Neoadjuvant Chemoradiation

With Gemcitabine Versus Upfront Surgery in Patients With Borderline Resectable
Pancreatic Cancer: A Prospective, Randomized, Open-label, Multicenter Phase 2/3
Trial. Ann Surg 2018; 268(2):215-222.

7. Murphy JE, Wo JY, Ryan DP, et al. Total Neoadjuvant Therapy With FOLFIRINOX
Followed by Individualized Chemoradiotherapy for Borderline Resectable Pancreatic
Adenocarcinoma: A Phase 2 Clinical Trial. JAMA Oncol 2018; 4(7):963-969.

8. Oba A, Ho F, Bao QR, et al. Neoadjuvant Treatment in Pancreatic Cancer. Front

Oncol 2020; 10:245.

9. Muller PC, Frey MC, Ruzza CM, et al. Neoadjuvant Chemotherapy in Pancreatic
Cancer: An Appraisal of the Current High-Level Evidence. Pharmacology 2020:1-11.

10. Versteijne E, Vogel JA, Besselink MG, et al. Meta-analysis comparing upfront
surgery with neoadjuvant treatment in patients with resectable or borderline resectable
pancreatic cancer. Br J Surg 2018; 105(8):946-958.

11. Janssen QP, Buettner S, Suker M, et al. Neoadjuvant FOLFIRINOX in Patients With
Borderline Resectable Pancreatic Cancer: A Systematic Review and Patient-Level
Meta-Analysis. J Natl Cancer Inst 2019; 111(8):782-794.

Copyright © 2021 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
 12. Delpero JR, Boher JM, Sauvanet A, et al. Pancreatic adenocarcinoma with venous
involvement: is up-front synchronous portal-superior mesenteric vein resection still
justified? A survey of the Association Francaise de Chirurgie. Ann Surg Oncol 2015;
22(6):1874-83.

13. Pietrasz D, Turrini O, Vendrely V, et al. How Does Chemoradiotherapy Following

Induction FOLFIRINOX Improve the Results in Resected Borderline or Locally
Advanced Pancreatic Adenocarcinoma? An AGEO-FRENCH Multicentric Cohort.
Ann Surg Oncol 2019; 26(1):109-117.

14. von Elm E, Altman DG, Egger M, et al. The Strengthening the Reporting of
Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting
observational studies. Lancet 2007; 370(9596):1453-7.

15. Raptis DA, Mettler T, Fischer MA, et al. Managing multicentre clinical trials with
open source. Inform Health Soc Care 2014; 39(2):67-80.

16. Clavien PA, Barkun J, de Oliveira ML, et al. The Clavien-Dindo classification of
surgical complications: five-year experience. Ann Surg 2009; 250(2):187-96.

17. Clavien PA, Vetter D, Staiger RD, et al. The Comprehensive Complication Index
(CCI(R)): Added Value and Clinical Perspectives 3 Years "Down the Line". Ann Surg
2017; 265(6):1045-1050.

18. The Royal College of Pathologists. Standards and minimumdatasets for reporting
cancers. Minimum dataset for the histo-pathologic reporting of pancreatic, ampulla of
Vater and bileduct carcinoma. 2019.

19. Janssen QP, O'Reilly EM, van Eijck CHJ, et al. Neoadjuvant Treatment in Patients
With Resectable and Borderline Resectable Pancreatic Cancer. Front Oncol 2020;
10:41.

20. Ghaneh P, Palmer DH, Cicconi S, et al. ESPAC-5F: Four-arm, prospective,

multicenter, international randomized phase II trial of immediate surgery compared
with neoadjuvant gemcitabine plus capecitabine (GEMCAP) or FOLFIRINOX or
chemoradiotherapy (CRT) in patients with borderline resectable pancreatic cancer.
Journal of Clinical Oncology 2020; 38(15_suppl):4505-4505.

21. Versteijne E, Suker M, Groothuis K, et al. Preoperative Chemoradiotherapy Versus

Immediate Surgery for Resectable and Borderline Resectable Pancreatic Cancer:
Results of the Dutch Randomized Phase III PREOPANC Trial. J Clin Oncol 2020;
38(16):1763-1773.

Copyright © 2021 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
 22. Ducreux M, Cuhna AS, Caramella C, et al. Cancer of the pancreas: ESMO Clinical
Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2015; 26 Suppl
5:v56-68.

23. Khorana AA, McKernin SE, Berlin J, et al. Potentially Curable Pancreatic
Adenocarcinoma: ASCO Clinical Practice Guideline Update. J Clin Oncol 2019;
37(23):2082-2088.

24. Giovinazzo F, Soggiu F, Jang JY, et al. Gemcitabine-Based Neoadjuvant Treatment in

Borderline Resectable Pancreatic Ductal Adenocarcinoma: A Meta-Analysis of
Individual Patient Data. Front Oncol 2020; 10:1112.

25. Cloyd JM, Heh V, Pawlik TM, et al. Neoadjuvant Therapy for Resectable and
Borderline Resectable Pancreatic Cancer: A Meta-Analysis of Randomized
Controlled Trials. J Clin Med 2020; 9(4).

26. Murphy JE, Wo JY, Ryan DP, et al. Total Neoadjuvant Therapy With FOLFIRINOX
in Combination With Losartan Followed by Chemoradiotherapy for Locally
Advanced Pancreatic Cancer: A Phase 2 Clinical Trial. JAMA Oncol 2019.

27. Maxwell JE, Katz MHG. Radiotherapy for Resectable and Borderline Resectable
Pancreas Cancer: When and Why? J Gastrointest Surg 2020.

28. Aad G, Abbott B, Abdallah J, et al. Search for new particles in two-jet final states in 7
TeV proton-proton collisions with the ATLAS detector at the LHC. Phys Rev Lett
2010; 105(16):161801.

29. Katz MH, Wang H, Balachandran A, et al. Effect of neoadjuvant chemoradiation and
surgical technique on recurrence of localized pancreatic cancer. J Gastrointest Surg
2012; 16(1):68-78; discussion 78-9.

30. Wu W, He J, Cameron JL, et al. The impact of postoperative complications on the

administration of adjuvant therapy following pancreaticoduodenectomy for
adenocarcinoma. Ann Surg Oncol 2014; 21(9):2873-81.

31. Kleeff J, Costello E, Jackson R, et al. The impact of diabetes mellitus on survival
following resection and adjuvant chemotherapy for pancreatic cancer. Br J Cancer
2016; 115(7):887-94.

32. Chu CK, Mazo AE, Goodman M, et al. Preoperative diabetes mellitus and long-term
survival after resection of pancreatic adenocarcinoma. Ann Surg Oncol 2010;
17(2):502-13.

33. Li D, Yeung SC, Hassan MM, et al. Antidiabetic therapies affect risk of pancreatic
cancer. Gastroenterology 2009; 137(2):482-8.

Copyright © 2021 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
 34. Salvia R, Malleo G, Maggino L, et al. Pancreatic ductal adenocarcinoma: time for a
neoadjuvant revolution? Updates Surg 2020; 72(2):321-324.

FIGURE LEGENDS

Figure 1. 1A Variation of administration of neoadjuvant therapy among different centers. 1B

Variation of type of neoadjuvant therapy administered during the inclusion period among
participating centers.

Figure 2. 2A. The impact of neoadjuvant therapy in overall survival of patients (n=1192, no
missing data, median follow up 34 months). 2B The impact of neoadjuvant chemotherapy
(NAC) and chemoradiotherapy (NACRT) on overall survival of patients (n=1192, no missing
data, median follow up 34 months).

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 Figure 3. Multivariable Cox regression analysis for overall survival

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 Table 1. Patient and operative characteristics
(n=1192) (n=317) (n=875)
Parameters All patients NAT No NAT OR p value
(95%CI)
Continent, n (%)
Asia 75 (6.3) 22 (6.9) 53 (6.1) - 0.1156*
Europe 914 (76.7) 237 (74.8) 677 (77.4) - -
North America 158 (13.3) 51 (16.1) 107 (12.2) - -
South America 45 (3.7) 7 (2.2) 38 (4.3)
Female sex, n (%) 572 (48) 164 (51.7) 408 (46.6) 0.81 (0.6- 0.1313
1.06)
Age, median (IQR) years 68 (60-73) 64 (57-71) 68 (61-74) - <0.001
BMI, median (IQR) kg/m2 23.8 (21.8- 24.9 (21-26) 24.0 (22-27) - 0.19
26.6)
Neoadjuvant 131 131 - - -
radiochemotherapy, n (%)
ASA-PS Grade ≥3, n (%) 330 (27.7) 80 (25.2) 250 (28.6) 0.844 0.2722
(0.62-1.14)
Comorbidities, n (%)
Cardiac Disease 157 (13.2) 39 (12.3) 118 (13.5) 0.900 0.629
(0.60-1.34)
Diabetes mellitus 350 (29.4) 83 (26.2) 267 (30.5) 0.807 0.150
(0.60-1.09)
Chronic renal failure 20 (1.7) 2 (0.6) 18 (2.1) 0.302 0.124
(0.03-1.28)
Metastatic cancer 19 (1.6) 7 (2.2) 12 (1.4) 1.623 0.303
(0.54-4.52)
Cirrhosis 9 (0.8) 1 (0.3) 8 (0.9) 0.343 0.458
(0.007-
2.58)
Stroke 27 (2.3) 4 (1.3) 23 (2.6) 0.473 0.191
(0.12-1.40)
COPD 55 (4.6) 43 (3.8) 12 (4.9) 0.761 0.531
(0.36-1.50)
Asthma 32 (2.7) 7 (2.2) 25 (2.9) 0.767 0.685
(0.28-1.85)
Operative time, median 399 (320- 410 (307- 392 (323-480) - 0.63
(IQR) minutes 485) 495)
Perioperative blood 0 (0-2) 0 (0-2) 0 (0-2) - 0.235
transfusion, median (IQR)

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 Type of portal vein
reconstruction, n (%)
Tangential resection 627 (52.6) 180 (56.8) 447 (51.1) - 0.1272*
Segmental resection 548 (46) 131 (41.3) 417 (47.7) -
Other reconstruction 17 (1.4) 6 (1.9) 11 (1.3) -
Pancreas texture (n=851
recorded), n (%)
Hard 693 (81.4) 211 (84.1) 482 (80.3) - 0.2105
Soft 158 (18.6) 40 (15.9) 118 (19.7) -
Pancreatic anastomosis, n
(%)
Pancreatojejunostomy 1117 (93.7) 305 (96.2) 812 (92.8) - 0.031
Pancreaticogastrostomy 75 (6.3) 12 (3.8) 63 (7.2) - -
Use of pancreatic stent
(n=993 recorded), n (%)
Pancreatic stent 340 (34.2) 77 (28) 263 (36.6) - 0.011
No pancreatic stent 653 (65.8) 198 (72) 455 (63.4) - -

* x2 test for comparison of two variables with more than two values, refers to all comparisons

NAT: neo adjuvant treatment; OR: odds ratio; CI: confidence intervals; BMI: body mass
index; IQR: interquartile range; ASA-PS: American Society of Anesthesiologists –
Performance Status; COPD: chronic obstructive pulmonary disease;

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 Table 2. Histopathology and postoperative characteristics
(n=1192) (n=317) (n=875)
Parameters All patients NAT No NAT OR p value
(95%CI)
Tumor size, median (IQR) cm 3 (2.3-3.5) 2.7 (2-3.5) 3 (2.5- - 0.0075
3.8)
N+ disease (n=1146 reported), n (%) 856 (74.7) 180 (57) 676 (81.4) <0.001
Total number of lymph nodes resected, 19 (13-30) 24.5 (17.4) 23 (14.9) - 0.099
mean (IQR) mm
Tumor grade (n=1124 recorded), n <0.001
(%) *
Well–differentiated/G1 137 (12.2) 43 (14.6) 94 (11.3)
Moderately differentiated/G2 659 (58.6) 147 49.8) 512 (61.8)
Poorly differentiated/G3 259 (23) 48 (16.3) 211 (25.5)
Undifferentiated/G4 3 (0.3) 1 (0.3) 2 (0.2)
Not assessed 66 (5.9) 56 (19) 10 (1.2)
Lymphovascular invasion, (n=1123 783 (69.7) 176 (58.1) 607 (74) 0.49 (0.37- <0.001
reported), n (%) 0.65)
Perineural invasion (n=1154 reported), 987 (86.4) 236 (77.1) 751 (88.6) 0.43 (0.31- <0.001
n (%) 0.62)
UICC Stage (n= 1130 reported), n (%) 0.3*
0 2 (0.2) 2 (0.7) 0 (0)
IA 39 (0.3) 22 (7.2) 17 (2.1)
IB 44 (3.9) 23 (7.5) 21 (2.5)
IIA 191 (16.9) 79 (25.8) 112 (13.6)
IIB 794 (70.3) 168 (54.9) 626 (76)
III 35 (3.1) 4 (1.3) 31 (3.8)
V 25 (2.2) 8 (2.6) 17 (2.1)
Portal vein involvement /invasion on
histology, n (%)
No involvement 661 (55) 217 (68.5) 444 (50.7) - <0.001
Involvement 531 (45) 100 (31.5) 431 (49.3) - -
Resection margin status, (n=1160
reported), n (%)
R0 574 (49.5) 177 (57.5) 397 (46.6) - 0.004*
R1 546 (47.1) 121 (39.3) 425 (49.9) - -
R2 40 (3.4) 10 (3.2) 30 (3.5) - -

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 Length of hospital stay, median (IQR) 12 (8-18) 11 (7-17) 12 (8-18) - 0.198
days
Complication >2 CD at discharge, n 236 (19.8) 67 (21.1) 169 (19.3) - 0.510
(%)
Complication >3a CD at discharge, n 123 (10.3) 36 (11.4) 87 (9.9) - 0.517
(%)
Pancreatic fistula, any grade, n (%) 156 (13.1) 24 (7.6) 132 (15.1) - 0.0004
5
Pancreatic fistula, grades B & C, n (%) 89 (7.5) 16 (5) 73 (8.3) - 0.061
CCI® at discharge, n (%) 21 (0-29.6) 21 (0-30) 21 (0-30) - 0.895
CCI® at 30 days, n (%) 21 (0-29.6) 21 (0-31) 21 (0-30) - 0.185
In hospital mortality, n (%) 33 (2.8) 8 (2.5) 25 (2.9) - 0.844
Complication >2 CD at 30 days, n (%) 260 (21.8) 79 (24.9) 181 (20.7) - 0.131
Complication >3a CD at 30 days, n 135 (11.3) 42 (13.2) 93 (10.6) - 0.2151
(%)
Complication >2 CD at 90 days, n (%) 273 (22.9) 83 (26.2) 190 (21.7) - 0.118
Complication >3a CD at 90 days, n 140 (11.7) 43 (13.6) 97 (11.1) - 0.262
(%)
Adjuvant chemotherapy, n (n=1068 804 (75.3) 208 (69.6) 596 (77.5) 0.66 (0.49-
recorded), n (%) 0.91) 0.009
Reason for no adjuvant chemotherapy, 0.29*
n (%)
MDT decision 23 (8.6) 12 (13.3) 11 (6.3)
Patient wish 41 (15.5) 11 (12.2) 30 (32.8)
Poor performance status 70 (26.5) 20 (22.2) 50 (28.7)
Death 34 (12.9) 11 (12.2) 23 (13.2)
Unknown to center 96 (36.5) 36 (40) 60 (34.5)
Adjuvant radiotherapy, n (n=885 129 (14.5) 35 (13.3) 94 (15.1) 0.86 (0.55-
recorded) 1.32) 0.533

* x2 test for comparison of two variables with more than two values, refers to all comparisons

NAT: neo adjuvant treatment; OR: odds ratio; CI: confidence intervals; IQR: interquartile
range; UICC: Union for International Cancer Control; SMA: superior mesenteric artery;
SMV: superior mesenteric vein; CD: Clavien-Dindo classification; CCI®: comprehensive
complication index; MDT: multidisciplinary tumor board.

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