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Management of distal cholangiocarcinoma with arterial involvement: Systematic review and case series on the role of neoadjuvant therapy

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Background: The use of neoadjuvant therapy (NAT) in distal cholangiocarcinoma (dCCA) with regional arterial or extensive venous involvement, is not widely accepted and evidence is sparse. Aim: To synthesise evidence on NAT for dCCA and present the experience of a high-volume tertiary-centre managing dCCA with arterial involvement. Methods: A systematic review was performed according to PRISMA guidance to identify all studies reporting outcomes of patients with dCCA who received NAT. All patients from 2017 to 2022 who were referred for NAT for dCCA at our centre were retrospectively collected from a prospectively maintained database. Baseline characteristics, NAT type, progression to surgery and oncological outcomes were collected. Results: Twelve studies were included. The definition of "unresectable" locally advanced dCCA was heterogenous. Four studies reported outcomes for 9 patients who received NAT for dCCA with extensive vascular involvement. R0 resection rate ranged between 0 and 100% but without survival benefit in most cases. Remaining studies considered either NAT in resectable dCCA or inclusive with extrahepatic CCA. The presented case series includes 9 patients (median age 67, IQR 56-74 years, male:female 5:4) referred for NAT for borderline resectable or locally advanced disease. Three patients progressed to surgery and 2 were resected. One patient died at 14 months with evidence of recurrence at 6 months and the other died at 51 months following recurrence 6 months post-operatively. Conclusion: Evidence for benefit of NAT is limited. Consensus on criteria for uniform definition of resectability for dCCA is required. We propose using the established National-Comprehensive-Cancer-Network® criteria for pancreatic ductal adenocarcinoma.
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WJGS https://www.wjgnet.com 2689 August 27, 2024 Volume 16 Issue 8
World Journal of
Gastrointestinal Surgery
W J G S
Submit a Manuscript: https://www.f6publishing.com World J Gastrointest Surg 2024 August 27; 16(8): 2689-2701
DOI: 10.4240/wjgs.v16.i8.2689 ISSN 1948-9366 (online)
SYSTEMATIC REVIEWS
Management of distal cholangiocarcinoma with arterial involvement:
Systematic review and case series on the role of neoadjuvant
therapy
Lewis A Hall, Duncan Loader, Santiago Gouveia, Marta Burak, James Halle-Smith, Peter Labib, Moath
Alarabiyat, Ravi Marudanayagam, Bobby V Dasari, Keith J Roberts, Syed S Raza, Michail Papamichail, David
C Bartlett, Robert P Sutcliffe, Nikolaos A Chatzizacharias
Specialty type: Surgery
Provenance and peer review:
Invited article; Externally peer
reviewed.
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Novelty: Grade B
Creativity or Innovation: Grade B
Scientific Significance: Grade A
P-Reviewer: Piltcher-da-Silva R
Received: March 15, 2024
Revised: May 28, 2024
Accepted: June 27, 2024
Published online: August 27, 2024
Processing time: 154 Days and 2.7
Hours
Lewis A Hall, Santiago Gouveia, Marta Burak, James Halle-Smith, Peter Labib, Moath Alarabiyat,
Ravi Marudanayagam, Bobby V Dasari, Keith J Roberts, Syed S Raza, Michail Papamichail, David
C Bartlett, Robert P Sutcliffe, Nikolaos A Chatzizacharias, Department of Hepatopancreatobiliary
Surgery and Liver Transplantation, University Hospitals Birmingham NHS Foundation Trust,
Birmingham B15 2GW, United Kingdom
Lewis A Hall, James Halle-Smith, Keith J Roberts, Institute of Immunology and Immunotherapy,
University of Birmingham, Birmingham B15 2TT, United Kingdom
Duncan Loader, College of Medical and Dental Sciences, University of Birmingham,
Birmingham B15 2TT, United Kingdom
Nikolaos A Chatzizacharias, Institute of Clinical Sciences, University of Birmingham,
Birmingham B15 2TT, United Kingdom
Corresponding author: Nikolaos A Chatzizacharias, BM BCh, FACS, FRCS, PhD, Surgeon,
Department of Hepatopancreatobiliary Surgery and Liver Transplantation, University Hospitals
Birmingham NHS Foundation Trust, Mindelsohn Way, Birmingham B15 2GW, United
Kingdom. chatzizacharias@gmail.com
Abstract
BACKGROUND
The use of neoadjuvant therapy (NAT) in distal cholangiocarcinoma (dCCA) with
regional arterial or extensive venous involvement, is not widely accepted and evi-
dence is sparse.
AIM
To synthesise evidence on NAT for dCCA and present the experience of a high-
volume tertiary-centre managing dCCA with arterial involvement.
METHODS
A systematic review was performed according to PRISMA guidance to identify all
studies reporting outcomes of patients with dCCA who received NAT. All
patients from 2017 to 2022 who were referred for NAT for dCCA at our centre
were retrospectively collected from a prospectively maintained database. Baseline
Hall LA et al. NAT for dCCA with arterial involvement
WJGS https://www.wjgnet.com 2690 August 27, 2024 Volume 16 Issue 8
characteristics, NAT type, progression to surgery and oncological outcomes were collected.
RESULTS
Twelve studies were included. The definition of “unresectable” locally advanced dCCA was heterogenous. Four
studies reported outcomes for 9 patients who received NAT for dCCA with extensive vascular involvement. R0
resection rate ranged between 0 and 100% but without survival benefit in most cases. Remaining studies
considered either NAT in resectable dCCA or inclusive with extrahepatic CCA. The presented case series includes
9 patients (median age 67, IQR 56-74 years, male:female 5:4) referred for NAT for borderline resectable or locally
advanced disease. Three patients progressed to surgery and 2 were resected. One patient died at 14 months with
evidence of recurrence at 6 months and the other died at 51 months following recurrence 6 months post-
operatively.
CONCLUSION
Evidence for benefit of NAT is limited. Consensus on criteria for uniform definition of resectability for dCCA is
required. We propose using the established National-Comprehensive-Cancer-Network® criteria for pancreatic
ductal adenocarcinoma.
Key Words: Cholangiocarcinoma; Neoadjuvant therapy; Arterial involvement; Locally advanced; Systematic review
©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
Core Tip: Use of neoadjuvant therapy in distal cholangiocarcinoma (dCCA) with regional arterial or extensive venous
involvement, is not widely accepted and evidence is sparse. This systematic review highlights heterogeneity of definitions
and outcome reporting. Consensus on criteria for a uniform definition of resectability for dCCA is required to provide
homogenous reporting of pathways and outcomes. We propose the use of the already established National-Comprehensive-
Cancer-Network® criteria for pancreatic ductal adenocarcinoma and exemplify this with our case series. Future studies
should focus on international observational high-quality studies and prospective registries to account for the rare nature of
the disease.
Citation: Hall LA, Loader D, Gouveia S, Burak M, Halle-Smith J, Labib P, Alarabiyat M, Marudanayagam R, Dasari BV, Roberts KJ,
Raza SS, Papamichail M, Bartlett DC, Sutcliffe RP, Chatzizacharias NA. Management of distal cholangiocarcinoma with arterial
involvement: Systematic review and case series on the role of neoadjuvant therapy. World J Gastrointest Surg 2024; 16(8): 2689-2701
URL: https://www.wjgnet.com/1948-9366/full/v16/i8/2689.htm
DOI: https://dx.doi.org/10.4240/wjgs.v16.i8.2689
INTRODUCTION
Distal cholangiocarcinomas (dCCA) are tumours that arise in the common bile duct, below the confluence of the cystic
duct and above the ampulla of Vater[1,2], and comprise 30% of all CCA[1,3]. Surgical resection is the only curative
treatment for dCCA, though remains limited to early disease only, with just over a third of patients undergoing resection
[4]. A combination of gemcitabine and cisplatin is considered first-line systemic treatment for patient with unresectable
dCCA[5], with ongoing investigations into concurrent chemoradiotherapy (CRT)[6,7], triple-agent chemotherapy regi-
mens (with added nab-paclitaxel)[8,9], and immunotherapy[10]. Application of these regimens in the neoadjuvant setting
may downstage unresectable tumours, otherwise managed with palliative intent, to improve conversion rate to resection
with curative intent[11,12].
Use of neoadjuvant therapies (NAT) is now the standard of care for various malignancies, including borderline
resectable and locally advanced pancreatic ductal adenocarcinoma (PDAC)[13-15]. NAT tests tumour biology and
identifies patients who may be more likely to benefit from resection, offers improved completion rates when contrasted
with adjuvant delivery and may downstage the tumour to improve lymph node (LN) positivity and rates of margin
negative (R0) resection[16-18], resulting in improvement in overall survival (OS)[14]. The most widely accepted definition
of resectablity in PDAC is from the National Comprehensive Cancer Network® (NCCN®) and includes “resectable”,
“borderline resectable”, and ‘locally advanced’ and is graded on extent vascular involvement (Table 1)[15]. In contrast,
these staging terms in the context of dCCA are poorly defined and heterogenous in the literature. Similarly, a common
strategy for the management of dCCA with regional arterial or extensive venous involvement is less widely accepted.
Their similarities (in anatomy, surgical strategy, and chemotherapeutic response) might permit application of PDAC
evidence to the dCCA setting[18], especially considering diagnostic uncertainty, with some reviews suggesting resection
criteria are the same[19]. However, dedicated evidence for NAT in dCCA is necessary to define locally advanced disease
and optimise management strategy.
Hall LA et al. NAT for dCCA with arterial involvement
WJGS https://www.wjgnet.com 2691 August 27, 2024 Volume 16 Issue 8
Table 1 National Comprehensive Cancer Network Criteria defining resectablity at diagnosis for pancreatic ductal adenocarcinoma
Resectability
status Arterial Venous
Resectable No arterial tumour contact (CA, SMA, or CHA) No tumour contacts with the SMV or PV or ≤ 180°
contact without vein contour irregularity
Borderline
resectable
Pancreatic head/uncinate process: (1) Solid tumour contact with CHA
without extension to the CA or hepatic artery bifurcation allowing for safe
and complete resection and reconstruction; (2) Solid tumour contact with the
SMA of ≤ 180°; and (3) Solid tumour contact with variant arterial anatomy,
and the presence and degree of tumour contact should be noted if present, as
it may affect surgical planning. Pancreatic body/tail: Solid tumour contact
with the CA of ≤ 180°
Solid tumour contact with the SMV or PV of > 180°,
contact of ≤ 180° with contour irregularity of the vein or
thrombosis of the vein but with suitable vessel proximal
and distal to the site of involvement allowing for safe
and complete resection and vein reconstruction: Solid
tumour contact with the IVC
Locally
advanced
Pancreatic head/uncinate process: Solid tumour with > 180° degrees contact
with SMA or CA. Pancreatic body/tail: (1) Solid tumour contact > 180° with
the SMA or CA; and (2) Solid tumour contact with CA and aortic
involvement
Unreconstructible SMV or PV due to tumour
involvement or occlusion (thrombus tumour)
CA: Coeliac axis; SMA: Superior mesenteric artery; CHA: Common hepatic artery; SMV: Superior mesenteric vein; PV: Portal vein; IVC: Inferior vena cava.
This systematic review and case series aims to synthesise available evidence on the role of NAT for dCCA and present
the experience of a high-volume tertiary centre in the management of dCCA with arterial involvement.
MATERIALS AND METHODS
Design
The review was designed and performed in accordance with the PRISMA guidelines[20]. The PubMed database was
searched in December 2023 for published studies reporting on use of NAT in patients with CCA. No date restrictions
were used in the primary search. Reference lists of relevant studies were also cross-referenced to identify additional
studies. Key terms related to CCA and NAT, were used to complete the search. The initial search was kept broad to
ensure all relevant articles were captured and added for full text review. The complete search terms are available in
Supplementary material.
Study selection
The aim of the search strategy was to include all articles that described at least a subgroup of patients with dCCA and
their outcomes, with precedent for the search strategy from Grendar et al[21], who delivered an equivalent review on
hilar CCA. The rationale described by Grendar et al[21] included studies that detail the use of NAT for any indication (i.e.,
in resectable patients), with the assumption that the morbidity and mortality profile for resection after NAT will be
similar, independent of indication. Therefore, for this review, all studies that included original data on NAT in patients
with dCCA (even when grouped as extrahepatic CCA; eCCA) who subsequently underwent surgery were included.
Conference abstracts, literature reviews, animal studies, single case reports and articles not in the English language were
excluded, along with studies that reported outcomes for all CCA (including intrahepatic) without stratification.
Two reviewers (SG and MB) independently identified the studies for inclusion. Any discrepancies were identified and
resolved through discussion and third-party involvement (LH). The PRISMA flow diagram of included studies is shown
in Figure 1.
Data extraction
Data extraction points were pre-defined for both quantitative and qualitative elements, and three reviewers (LH, SG, and
MB) extracted data to a prepared template. A fourth reviewer assessed the data for completeness (JHS). Study character-
istics collected included country of origin, publication year and sample size. Type of NAT, indication for NAT, rate of
surgery and R0 resection, and survival outcomes were all collected. Finally, the conclusion of each study was
documented to deliver a narrative synthesis of current evidence of NAT for dCCA. Evidence Grade of Recommendations,
Assessment, Development and Evaluation (GRADE) was assessed according to the Cochrane GRADE approach[22].
Statistical analysis
Results were summarized in a narrative synthesis and descriptive statistics were provided where indicated.
Case series
All patients from 2017 to 2022 with dCCA with arterial involvement at our centre that were referred for NAT were
retrospectively collected from a prospectively maintained database. Baseline characteristics, disease stage, NAT type,
progression to surgery and survival data were all collected. Descriptive statistics were used to display demographic
variables. Continuous data was expressed as median (interquartile range, IQR), and categorical variables presented as
Hall LA et al. NAT for dCCA with arterial involvement
WJGS https://www.wjgnet.com 2692 August 27, 2024 Volume 16 Issue 8
Figure 1 PRISMA flow chart.
numbers and/or percentages. Where conducted, statistical analysis was completed using SPSS (IBM Corp. Released 2020.
IBM SPSS Statistics for Windows, Version 27.0. Armonk, NY, United States: IBM Corp).
RESULTS
Review
The systematic literature search yielded 2573 records. Full text screening was performed for 61 records. Twelve studies
were included in the final systematic review. The premier study was published in 1997[23], with the latest publications
over two decades later in 2023[24]. Eight of twelve studies were from the United States, with two studies from Japan and
two from South Korea. Study characteristics are presented in Table 2.
Studies design
Nine of twelve studies were retrospective, with four of these utilising national datasets. The remaining three studies were
prospective, with two defined as Phase I trials. Study rationale was heterogenous, with variability in comparator groups
(where present), choice of NAT and patient cohort.
Five studies compared NAT to surgery alone and two to surgery with adjuvant chemotherapy. Five studies did not use
a comparator. The type of NAT used was variable, broadly split between chemotherapy alone and CRT when reported.
The four studies reporting on national data cited inability to define NAT agents used as a limitation. Adam et al[25]
suggested that there was a “likelihood” that patients with eCCA treated with NAT were initially misdiagnosed as PDAC,
and therefore principal agents would be FOLFIRNOX or Gemcitabine/Abraxane.
Selected patient cohort was the most heterogenous aspect of the included studies, largely secondary to vague
definitions. Four studies report number of patients with locally advanced/unresectable dCCA who underwent upfront
chemotherapy (either with neoadjuvant or palliative intent) and subsequently had resection. A further four report
outcomes for patients with any (including resectable) dCCA who received NAT. Remaining studies treated eCCA as a
whole cohort, including both hilar and distal disease.
Outcomes
Studies that report outcomes on NAT for unresectable dCCA: Amongst the four studies that report outcomes of patients
who received NAT for unresectable dCCA, a total of 19 patients are included[23,26-28]. The definition of unresectability
was heterogenous across the four studies. McMasters et al[23] reported 4 patients who received NAT for “unresectable
disease” and subsequently underwent resection. No formal definition of “unresectability” was given, though grading was
based on radiographic imaging or exploratory surgery. All patients had R0 resection, with one shown to have a
pathological complete response (PCR). Only minor surgical complications were reported (3 wound infections and 1
arrhythmia). When compared to patients that had upfront resection, there was no difference in OS and the authors state
that all NAT patients died “within a relatively short period of time”, without specific quantification. Cloyd et al[26] report
Hall LA et al. NAT for dCCA with arterial involvement
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Table 2 Characteristics of included studies
Ref. Country Study type NAT type n
(total)
n
(distal)
n
(NAT,
distal)
n
(unresectable,
distal, NAT)
n (advanced
vascular
involvement,
distal, NAT)
n (unresectable,
distal, NAT,
resected)
McMasters
et al[23],
1997
United
States
Prospective 5-FU CRT 91 28 4 4 4 4
Czito et al
[27], 2006
United
States
Prospective
(Phase I)
Eniluracil/5-FU CRT 3 3 3 2 2 1
Nelson et al
[31], 2009
United
States
Retrospective Fluoropyrimidine-
based CRT
45 NR NR NR NR NR
Kobayashi
et al[33],
2015
Japan Prospective
(Phase I)
Gem CRT 25 25 15 NR NR NR
Cloyd et al
[26], 2019
United
States
Retrospective Gem or 5-FU
Chemotherapy or 5-
FU, cap or Gem CRT
45 45 21 9 1 9
Oh et al[28],
2021
South
Korea
Retrospective Gem-based 12 4 4 4 2 4
Adam et al
[25], 2023
United
States
Retrospective NR 2514 25141157 NR NR NR
Fujii et al
[29], 2022
Japan Retrospective Gem CRT 16 16 16 NR NR NR
Parente et al
[30], 2023
United
States
Retrospective NR 9411 1953 271 NR NR NR
Toyoda et al
[32], 2023
United
States
Retrospective NR 6582 NR NR NR NR NR
Choi et al
[24], 2023
South
Korea
Retrospective Gem/Cis/nab-P
chemotherapy
129 NR NR NR NR 24 (+4)2
Silver et al
[34], 2023
United
States
Retrospective NR 8040 NR NR NR NR NR
1Adam et al[25] report on extrahepatic cholangiocarcinoma, in the context of peri-ampullary malignancy, without explicitly defining distal
cholangiocarcinoma.
2Choi et al[24] give a total number of patients with distal (24) and distal + hilar (4) patients who had locally advanced disease, who received NAT, and were
then resected, but without giving the individual numbers of each.
NAT: Neoadjuvant therapy; CRT: Chemoradiotherapy; FU: Fluorouracil; Gem: Gemcitabine; Cap: Capecitabine; nab-P: Nab-paclitaxel; NR: Not reported.
outcomes for 25 patients who receive NAT for various indications, of which nine were for “advanced disease”
[radiographic evidence of adenopathy (n = 6), locally advanced vascular anatomy (n = 1), markedly elevated
carbohydrate antigen 19-9 (CA19-9, n = 1), indeterminate liver lesion (n = 1)]. Other indications included poor
performance status (n = 7), misdiagnosis of PDAC (n = 3) and undetermined (n = 2). Ninety-five per cent of patients had
an R0 resection, and one patient had a PCR. Median OS was 40.3 [95% confidence interval (95%CI): 0-111.5] months in
patients who received NAT, vs 50.3 (95%CI: 0-101.8) months after surgery first approach (P > 0.05). Fourteen per cent of
patients who received NAT had local recurrence, vs 0% patients who proceeded straight to surgery. Czito et al[27] reports
2 patients who received NAT for “unresectable” dCCA. Unresectability was defined as “tumour involvement of the
superior mesenteric artery or coeliac axis, as well as encasement and/or thrombosis of the superior mesenteric vein or
portal vein”. One patient experienced a 33% reduction in tumour size and progressed to an R1 resection, the other patient
was found to have metastatic disease and did not proceed to surgery. Survival data specific to these patients is not
reported.
Oh et al[28] do not use the term NAT, but instead report on rate of “conversion surgery” following palliative
chemotherapy for unresectable eCCA. Twelve patients with eCCA were commenced on palliative chemotherapy
regimens for unresectable disease; 4 patients had dCCA. Two patients were graded unresectable due to local LN
enlargement, and 2 due to extensive vascular involvement (1 due to portal vein and superior mesenteric vein invasion
with superior mesenteric artery abutment, and 1 due to portal vein abutment). Three patients received gemcitabine-based
chemotherapy, and 1 patient received FOLFIRINOX due to initial misdiagnosis of PDAC. All 4 patients were converted to
an R0 resection, 2 were alive at last follow up (12 and 17 months) without evidence of recurrence, and 2 had died at 7 and
24 months, with the former experiencing recurrence at 9 months post-operatively.
Hall LA et al. NAT for dCCA with arterial involvement
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Studies that report outcomes on patients commenced on NAT for dCCA of any stage: Two studies report outcomes for
patients commenced on NAT for dCCA of any resectability stage[29,30]. Parente et al[30], reported data on 271 patients
with dCCA who received a resection after NAT from the United States National Cancer Database. No indications on the
reasoning for NAT use were reported. Sixty-three (23.2%) patients who received NAT had American Joint Committee on
Cancer (AJCC) grade T3 or above. Eighty one percent of patients who received NAT had an R0 resection, vs 78% and 67%
in surgery alone, and with adjuvant chemotherapy respectively. NAT significantly improved survival [Hazard ratio (HR):
0.65; 95%CI: 0.53-0.78, P < 0.001], when compared to upfront resection. OS was 38.1 months, vs 21.8 (surgery alone) and
28.0 months (adjuvant chemotherapy). The authors acknowledge that it is likely most patients who received NAT did so
due to locally advanced disease, but a definition is not given, and specific numbers cannot be derived.
Fujii et al[29] investigated the impact of NAT on body composition and sarcopenia in 16 patients with resectable dCCA.
All patients underwent R0 resection. Three-year OS was reported as 100% for patients without sarcopenia vs 71% in
patient with sarcopenia (P = 0.115), and disease-free survival (DFS) was 100% in patients without sarcopenia vs 50% (P =
0.025) in sarcopenic patients.
Studies that report outcomes on NAT for any eCCA (including distal and hilar disease): Remaining studies report
outcomes for all eCCA, including hilar tumours. Three studies stratify by resectability and three report on NAT in all
eCCA. Nelson et al[31] describe 10 patients who received NAT for locally advanced or borderline resectable disease
(assessed radiographically) and 2 patients due to surgeon preference. The authors do not specify the radiological or other
criteria used to define locally advanced or borderline resectable disease. Amongst the 12 patients, 91% had an R0
resection; a quarter of patients had a PCR. When compared to patients who had upfront resection with adjuvant
chemotherapy, 5-year-OS was 53% (NAT) vs 23% (upfront resection/adjuvant chemotherapy). Choi et al[24] included 95
patients with locally advanced eCCA who received NAT. Locally advanced disease was defined by the lack of distant
metastatic disease and local vessel involvement that however is mainly applicable to hilar CCA. Sixty per cent were
considered resectable following NAT and of these, 91.2% had an R0 resection. The authors specify that of the resected
patients, 24 had distal disease with 4 patients having PCR in the pathology report. Further outcome data is not specific to
distal disease, however.
Toyoda et al[32] identified 70 patients with eCCA who received NAT across a decade (2006-2017). The proportion of
patients who received NAT for eCCA increased from 1.2% to 2.1% over this time. Overall, there was no significant effect
on survival when compared to upfront resection (median OS 26 for NAT vs 23 months for upfront resection). However,
when patients were stratified according to the disease stage as per AJCC, patients with advanced disease (stage III/IVa)
experienced a significant survival benefit (HR: 0.53; 95%CI: 0.30-0.92, P = 0.02).
Kobayashi et al[33] aimed to assess the safety of NAT in any patient with biliary tract cancer, actively excluding
patients with “major vessel involvement”. Fifteen patients with dCCA received NAT and 3-year-OS was 75.2%. R0 rate
for any patient who received NAT (all biliary tract cancers) was 96%. Adam et al[25] looked to describe patterns of NAT
use in CCA, comparing outcomes to upfront resection. One hundred and fifty-seven patients with eCCA were identified
retrospectively using national data. No included patients had a disease stage greater than AJCC stage II. Eighty-three per-
cent of patients had an R0 resection vs 76% who had upfront resection. NAT also improved survival, with median OS of
38.4 (NAT) vs 25.6 months (upfront resection).
Silver et al[34] also utilised national datasets to explore NAT use in all eCCA. Overall, they report an increase in NAT
use from 0.5% in 2004, to 5.8% in 2017. NAT improved rate of R0 resection [Odds ratio (OR): 1.49; 95%CI: 1.10-2.02] and
mOS, at 35.1 months vs 25.3 months with surgery alone. The authors stratified according to chemotherapy or CRT and
found that CRT improved R0 rate (OR: 3.52; 95%CI: 2.11-5.86) and showed longest mOS of 47.8 months.
GRADE scoring
GRADE scoring was completed for all included studies. Three studies were considered “moderate”, six “low”, and three
“very low”. A summary of study conclusions with assigned GRADE Score and rationale are shown in Table 3.
Case series
From 2017 to 2023, 9 patients with borderline resectable or locally advanced dCCA received NAT at our centre and are
included in the present study (median age 67, IQR 56-74 years, male:female 5:4). The definitions used for radiological
staging were the same as the NCCN definitions for PDAC[15]. All cases were discussed in the HPB MDT. Staging invest-
igations included a computed tomography (CT) with contrast of the chest abdomen and pelvis for all patients and a
magnetic resonance tomography of the liver. Positron emission tomography and CT (PET-CT) was selectively used if
there were concerns for metastatic disease on the CT.
Nine patients were referred for NAT: 1 died before receiving NAT, 4 did not progress to surgery, and 1 was lost to
follow up (the patient opted for private treatment at another centre). Of the remaining 3 patients, 2 received 6 cycles of
Gemcitabine and Cisplatin and 1 received only 4 cycles. On restaging, these 3 patients demonstrated disease stability with
no evidence of metastatic disease and progressed to surgery. One was found to have liver metastases intraoperatively,
and the other 2 patients underwent resection. The resections included a pancreaticoduodenectomy with extended right
hemi-hepatectomy and a total pancreatectomy with splenectomy, portal vein resection with interposition cadaveric vein
graft reconstruction and replaced common hepatic artery resection with end-to-end reconstruction (Figure 2). The first
patient had an R1 resection and histology revealed pathological stage T3N2M1 due to positive para-aortic LNs (TNM
stage M1). The latter patient had an R0 resection with evidence of partial response to NAT and histology showed T4N2
disease. Severe complications (Clavien-Dindo grade IIIa) were encountered only in the first case, where the patient had a
pancreatojejunostomy leak and required CT guided drainage of a collection. Length of stay was 36 and 13 days
Hall LA et al. NAT for dCCA with arterial involvement
WJGS https://www.wjgnet.com 2695 August 27, 2024 Volume 16 Issue 8
Table 3 Summary of study’s findings
Ref. Rationale Results Conclusions GRADE1
McMasters
et al[23],
1997
Premier paper on NAT in
eCCA; Initial experience;
NAT vs UR
4 dCCA received NAT for advanced disease; 100%
had R0 resection; 25% had PCR; No survival
difference between NAT vs UR; 100% died “within
relatively short period of time”
NAT is safe; NAT is
associated with a high rate
of PCR; NAT may improve
R0 rate; Encourages further
multicentre trials
Moderate: Few patients;
No definition of “locally
advanced”; Specific to
dCCA
Czito et al
[27], 2006
Dose determination for
novel CRT for resectable and
unresectable UGI cancers;
NAT only
3 dCCA received NAT; 1 (resectable) patient had
R0 resection and PCR; 1 (unresectable) had 33%
decreased in tumour size, underwent R1 resection;
1 was not resected due to metastatic disease;
Survival not reported
No specific conclusion on
NAT in dCCA
Very low: Few patients;
No comparator group;
Trial halted before
completion; Offers no
conclusion
Nelson et al
[31], 2009
Evaluation of CRT in
neoadjuvant setting for
eCCA; NAT vs AC
12 eCCA received NAT (hilar and distal); 10 had
NAT due to BLR or LA disease, 2 for surgeon
preference; 91% had R0 resection and 25% had
PCR; 5-year-OS: 53% vs 23%, despite more
advanced disease in NAT cohort
NAT affords local control
and enhances resectablity
and survival in eCCA
Low: Few patients; Only
includes resected
patients; Heterogenous
indication for NAT;
Includes hilar and distal
tumours
Kobayashi
et al[33],
2015
Assessment of safety of NAT
for all BTC; Assessment of
pathological effect of NAT
for BTC
15 dCCA received NAT (25 total); 96.0% R0
resection rate (total); 3-year-OS 75.2% for dCCA
NAT gemcitabine with RT
feasible to improve survival
and control regional
extension
Very low: Excluded
patients with major
vessel involvement;
Includes hilar and distal
tumours
Cloyd et al
[26], 2019
Pragmatic assessment of
NAT use in resected dCCA;
NAT vs UR
45 dCCA; 21 had NAT; 5/21 chemotherapy only,
10/21 CRT, 6/21 both; Varied indications for NAT;
95.0% had R0 resection; 1/21 had PCR; Median OS:
40.3 months UR vs 50.3 months UR; 14.3% NAT
had local recurrence vs 0% UR
Does not support routine
administration but
beneficial in advanced
disease or in patients with
poor PS
Moderate: Only includes
resected patients;
Specific to dCCA
Oh et al
[28], 2021
Demonstration of feasibility
of conversion surgery after
palliative chemotherapy for
unresectable eCCA
12 eCCA, 4 dCCA commenced on palliative
chemotherapy; 2 patients deemed unresectable due
to LN enlargement, 1 due to PV/SMV invasion
with SMA abutment, and one due to PV abutment;
3 received Gem-based chemo, and 1 received
FOLFIRINOX, 2 also received radiotherapy; All 4
had R0 resection (100%); 2 were alive at last FU (12
and 68 months) and 2 had died (24 and 7 months);
Only one patient developed recurrence, 9 months
post-operatively (died at 24 months)
Conversion surgery is a
feasible and effective
treatment strategy in certain
unresectable CCAs
Moderate: Few patients;
Includes all patients with
initially unresectable
disease, specifying distal
disease; Chemo given
with palliative intent,
rather than NAT
Adam et al
[25], 2023
Describe pattern of NAT use
in CCA; NAT vs UR
157 eCCA received NAT; 24% were T downstaged;
9% were N downstaged; 83% NAT had R0
resection vs 76% UR; OS: 38.4 (NAT) months vs
25.6 (UR) months
NAT is associated with
downstaging, improved R0
resection and survival for
eCCA
Very low: Excluded
patients with advanced
disease; Uses national
database with hetero-
genous data; Includes
hilar and distal tumours
Fujii et al
[29], 2022
Investigate impact of NAT
CRT on body composition in
patients with dCCA
16 dCCA received NAT CRT, all resectable; 16
progressed to surgery, with 100% R0 rate; 6/16 had
significant AEs (grade > 3); 9/16 were sarcopenic
pre-NAT, 8/16 after NAT (one patient recovered
during NAT); 3-year-OS without sarcopenia: 100%
versus 71% with sarcopenia (NS); Patients with
sarcopenia had significantly shorter DFS (P =
0.025)
NAT CRT is safe in this
cohort and does not
significantly affect body
composition; Further
studies necessary to assess
impact of sarcopenia on OS
in biliary tract cancer
Low: Few patients;
Resectable only and no
indication for NAT given
Parente et al
[30], 2023
Evaluate role of NAT in each
subset of CCA, specifically
impact on survival; NAT vs
AC vs UR
271 CCA had NAT; 81% R0 resection rate, vs 78%
(UR) vs 67% (AC); Median OS 38.1% (NAT) vs
21.8% (UR) 28.0% (AC); NAT significantly
improved survival vs AC; HR: 0.65 (0.53-0.78), P <
0.001
NAT + resection vs UR
increased survival,
regardless of nodal or
margin status; Careful MDT
evaluation warranted for
NAT incorporation into
CCA management;
Multicentre trials needed
Low: Included distal
tumours only but no
indication for NAT
given; Only includes
resected patients; Uses
national database with
heterogenous data
Toyoda et al
[32], 2023
Characterize impact of NAT
on eCCA prognosis and
establish trends in
utilisation; NAT vs UR
70 eCCA received NAT; Over a decade, proportion
of NAT use increased from 1.2%-2.1%; Median OS
26 months UR vs 23 months UR; 5-year-survival
21.5% UR vs 25.5% UR; Advanced Stage eCCA OS
HR: 0.53 (0.30-0.92), P = 0.02
Use of NAT in CCA
remains low but is
increasing; No overall
benefit, however beneficial
in advanced disease
Low: Includes hilar and
distal tumours; Uses
national database with
heterogenous data
Assessment of effectiveness
of local (improved chance of
surgery with curative intent)
and systemic disease
(reduced risk of metastasis)
Choi et al
[24], 2023
95 eCCA had NAT; 60.0% were resectable
following NAT; 91.2% had R0 resection; 24 dCCA
were resected + 4 distal and hilar; 4 dCCA had
PCR
Triplet chemotherapy has
acceptable safety profile;
Clear downstaging effect in
LA disease
Low: Includes hilar and
distal tumours
Hall LA et al. NAT for dCCA with arterial involvement
WJGS https://www.wjgnet.com 2696 August 27, 2024 Volume 16 Issue 8
control using a triplet
chemotherapy; Locally
advanced CCA
Silver et al
[34], 2023
Characterize NAT trends
over time in eCCA; Identify
factors associated with NAT
use; NAT impact on
outcomes
417 eCCA received NAT (215 chemo only versus
202 CRT); Increase from 0.5% to 5.8% of NAT use
across study time frame (2004-2017); NAT
improved R0 resection rate (OR: 1.49; 95%CI: 1.10-
2.02) and longer mOS (35.1 months vs 25.3 months)
vs surgery alone; NAT CRT improved R0 rate (OR:
3.52, 95%CI: 2.11-5.86) and showed longest mOS of
47.8 months, with improvement in OS of HR: 0.64,
95%CI: 0.52-0.79 vs surgery alone
NAT, especially NAT CRT,
is associated with improved
post-operative outcomes
and increased survival in
eCCA
Low: Include distal and
hilar tumours; No
indication for NAT
given; Only includes
resected patients; Uses
national database with
heterogenous data
1Cochrane Grade of Recommendations, Assessment, Development and Evaluation (GRADE) approach.
NAT: Neoadjuvant therapy; CRT: Chemoradiotherapy; RT: Radiotherapy; AC: Adjuvant chemotherapy; UR: Upfront resection; dCCA: Distal
cholangiocarcinoma; eCCA: Extrahepatic cholangiocarcinoma; BTC: Biliary tract cancer; OS: Overall survival; PCR: Pathological complete response; HR:
Hazard ration; LA: Locally advanced.
Figure 2 Intraoperative image. Intraoperative image of vascular reconstruction after total pancreatectomy with splenectomy, portal vein resection with
interposition cadaveric vein graft, and replaced common hepatic artery resection, with end-to-end anastomosis.
respectively. The former patient died at 14 months from diagnosis (7 months post-operatively), with evidence of
recurrence via malignant cytology on ascitic drain at 6 months. The latter died at 51-months from diagnosis (36 months
post-operatively) following detection of peritoneal metastases at 6 months and evidence of locoregional, soft tissue
recurrence at the hilum and lung metastases 21 months post-operatively.
Of the 4 that did not progress to surgery, reasons for failure to progress included: Adverse effects of NAT (n = 2) and
failure to achieve disease control (n = 2). The median OS of patients who did not proceed to resection, with the exception
of one long survivor (39 months), was 5-months.
DISCUSSION
This study is an exhaustive review of the current landscape of NAT in dCCA. The included case series offers a small
addition of a tertiary centre experience, where an appropriate denominator (all patients referred for NAT) is provided.
Whilst existing literature defines 9 patients who had resection, for “unresectable” or “advanced” disease due to extensive
vascular involvement, this series is unique in reporting, together, a formal denominator and rate of progression to
surgery, and a definition of locally advanced disease. To the best of our knowledge, this series is also the first from the
United Kingdom.
Best oncological outcomes in cancers of the biliary tract are achieved by a combination of resectional surgery and
systemic treatment. Negative surgical resection margins are associated with improved oncological outcomes[35] hence
the debate on the management of tumours that involve regional vessels whether upfront surgery with concomitant
vascular resection followed by adjuvant treatment or NAT followed by resection offers better results. NAT offers the
Hall LA et al. NAT for dCCA with arterial involvement
WJGS https://www.wjgnet.com 2697 August 27, 2024 Volume 16 Issue 8
opportunity to test the disease biology[19] and is the standard of care in such cases of PDAC (borderline resectable and
locally advanced)[15]. In PDAC, as well as other cancers, NAT has been proven to confer a survival advantage, improve
the rate of negative resection margins and LN involvement[14]. Nonetheless, similar evidence in dCCA is scarce. To
complicate the situation further, in contrast to PDAC, in dCCA there are no widely accepted or used definitions to
radiologically stage the disease as borderline resectable or locally advanced. Other cited indications, such as initial
misdiagnosis of PDAC, also skew any findings[26], while dCCA-specific conclusions are also difficult to draw, as
outcomes are often reported by broad anatomical groups (i.e., eCCA)[24,31-33].
Definition of resectability
Our review demonstrated that unresectability in dCCA was rarely defined and where it was, a variety of definitions were
used. Cloyd et al[26] reported a combination of radiological (adenopathy, indeterminate liver lesions or advanced
vascular involvement) and elevated CA19-9 to define unresectability. Czito et al[27] defined advanced disease as “tumour
involvement of the superior mesenteric artery or coeliac axis, as well as encasement and/or thrombosis of the superior
mesenteric vein or portal vein”. Choi et al[24] defined locally advanced disease with a pentad of criteria, three of which
specific to extensive radiological vascular involvement, but are mainly applicable in cases of hilar CCA. Oh et al[28] report
the use of extensive vascular involvement and LN enlargement to individualise staging in their reported series. Whilst
the authors of these studies did not specify a validated classification system; the definitions used are comparable to the
NCCN criteria in PDAC[15]. Nelson et al[31] stated NAT was given for locally advanced or borderline resectable disease,
which was assessed radiographically, but do not define or cite criteria, and McMasters et al[23] do not give a definition of
“unresectable”. Remaining studies did not cite advanced disease as an indication for NAT. With such heterogeneity, or
indeed absence, of definition, drawing conclusions on benefit of NAT in advanced dCCA is difficult. In contrast to dCCA,
the anatomical criteria for non-resectable disease in the most common periampullary malignancy, PDAC, are very clearly
defined[16] though there remains room for debate[36]. In our series, we consistently used these criteria to define locally
advanced dCCA and utilised NAT for these cases. Since the anatomical constraints and inter-operative challenges are
similar in dCCA and PDAC, we propose the use of the PDAC NCCN staging criteria in preoperative staging of dCCA.
This will improve consistency in results reporting and generalisability of outcomes and conclusions in the management of
an advanced stage of this rare malignancy. It could be argued that regional LN involvement and biological criteria, such
as elevated CA19-9, should also be included in the definition. Both may be used surrogate markers of advanced disease
where NAT may be utilised, however neither determine resectability.
The majority of the data on the results of systemic treatment in CCA are reported in the adjuvant or palliative setting.
The landmark BILCAP study included all biliary tract cancers and demonstrated a survival benefit of adjuvant
capecitabine among resected patients, especially after adjusting for high risk factors[37]. The ABC-02 study was a phase 3
trial on advanced biliary tract cancer, whose results form the basis of the first-line recommendation of the combination of
gemcitabine and cisplatin for unresectable CCA, with mOS 11.7 months, vs 8.1 months with gemcitabine monotherapy
[5]. With median OS limited to less than one year even in patients receiving combination regime, further trials invest-
igated triplet therapy (Gemcitabine/cisplatin and nab-paclitaxel) and immunotherapy[8,9]. The TOPAZ-1 study
demonstrated a survival advantage (HR: 0.80; 95%CI: 0.66-0.97; P = 0.021) when durvalumab (a PD-L1 inhibitor) was
given with Gemcitabine/cisplatin vs Gemcitabine/cisplatin and placebo to patients with unresectable, locally advanced,
recurrent, or metastatic biliary tract cancer[10]. The KEYNOTE-966 study showed a similar survival advantage (HR: 0.83;
95%CI: 0.72-0.95, P = 0.0034), when pembrolizumab was added to the doublet chemotherapy[38]. Ulusakarya et al[39]
report a single-centre experience of NAT with FOLFIRINOX in advanced and metastatic biliary tract cancers (all types)
and 6 (14%) patients were converted to either R0 or R1 resection, with prospective trials are ongoing[40]. Whilst results
are promising for systemic therapy, specific data on their benefit in the neoadjuvant setting must be expanded.
Progression to surgery
In every NAT approach, an essential parameter is the number of patients who progressed to surgery after treatment.
Reporting this rate allows understanding of NAT tolerability, demonstrates feasibility of delivery and efficacy in systemic
disease control or even downstaging advanced disease for subsequent resection. Of the four studies that specifically
reported outcomes for NAT in unresectable dCCA, McMaster et al[23] report all patients who were commenced on NAT,
progressed to surgery. However, Cloyd et al[26] and Oh et al[28], only included patients who were resected, therefore the
number of patients that had disease progression or otherwise did not progress to surgery is unknown. Czito et al[27] only
includes 2 patients with unresectable dCCA who received NAT, and 1 progressed to resection (R1). Although not specific
to dCCA, rate of progression to surgery was reported by Choi et al[24], who report 60% were successfully downstaged
with NAT, where NAT was given for advanced disease. The authors used the number of patients who were commenced
on NAT as the denominator; with 73 of 129 (56.6%) patients progressing to surgery. A conversion rate of patients who
progress to surgery provides a broader picture of the treatment sequencing, and the concept was first introduced in the
context of resection following palliative chemotherapy in gastric cancer[41]. Further work reported it as an outcome in
pancreatic cancer[42-44] and even intrahepatic CCA[45]. Choi et al[24] contrast their rate of progression to surgery with a
previous study[8], that had a rate of only 20%. Two explanations are given by the authors: First, the included study
included only locally advanced patients, whilst the previous study also included patients with distant metastasis. Second,
in the previous study only 15.0% of patients had eCCA, whilst Choi et al[24], 73.6% patients had eCCA. Other studies
corroborate a higher rate of progression to surgery for eCCA than intrahepatic CCA in the NAT setting[9]. In our case
series, only 3 patients progressed to surgery and 2 had a resection following NAT. The 33% rate of progression to surgery
(22% to resection) in our series is markedly lower than the 56% reported by Choi et al[24]. Such disparity is likely
secondary to Choi et al[24] including all locally advanced eCCA, rather than just dCCA and the difference in definitions
of resectability. The difference in reported rates in the literature would be made more comparable if a unifying definition
Hall LA et al. NAT for dCCA with arterial involvement
WJGS https://www.wjgnet.com 2698 August 27, 2024 Volume 16 Issue 8
of resectability is used and outcomes on the management of dCCA are reported independently.
R0 resection rate for studies reporting on NAT for unresectable dCCA ranged between 0% and 100%[23,26-28].
Amongst the other included studies, R0 rate was reported to be between 81% and 96% following NAT, though this is
inclusive of hilar tumours, as well as resectable disease[24,25,30,31]. Once again, due to the heterogeneity in reporting it is
impossible for safe conclusion to be drawn.
Oncological outcomes
Included studies cannot provide definite oncological outcomes for advanced disease, specific to dCCA. Of those the four
studies that reported oncological outcomes for unresectable or locally advanced dCCA, Cloyd et al[26] report a median
OS of 40.3 months for patients who received NAT and progressed to surgery, with 3 patients developing local recurrence
and 8 developing distant recurrent disease. The DFS was not specified. Oh et al[28] reported the oncological outcomes for
4 patients with initially unresectable dCCA, with median OS of 18.0 months and DFS of 7.5 months following resection,
with 1 patient experiencing recurrence 9.0 months post-operatively. Amongst studies reporting outcomes for NAT in
eCCA, independent of a defined indication, median OS was between 26-38 months[25,30,32,34]. Kobayashi et al[33] report
a 3-year survival of 75% and Nelson et al[31] reported a 5-year survival of 53%. With 2 resected patients amongst our own
cohort, 1 patient survived fourteen months from diagnosis, and the other 51 months. Both patients experienced
recurrence at 6 months post-operatively. Considering the latter patient, such prolonged survival contrasts with an early
recurrence. Possible reasons may include misdiagnosis of recurrence on imaging follow-up or likely a favourable disease
biology. Amongst studies that compared oncological outcomes in patients receiving NAT and surgery, vs chemotherapy
alone, Oh et al[28] reported a median OS of 28 months for all included patients and stated that this is longer than previous
studies where patients received chemotherapy only, but do not offer a comparison within their own data. Choi et al[24],
however, highlighted a significantly longer survival for patients who progressed to surgery, than those who only
received chemotherapy, citing a 2-year overall rate of 45% vs 19% respectively (P = 0.032). In our own series, of the
patients who did not progress to surgery, median OS was only 5 months (with the exception of a lone, long survivor at 39
months).
Limitations
The main limitation is the lack of a widely accepted and commonly used definition on resectability of dCCA and the
pooling of data and outcomes for the management of locally advanced dCCA with all biliary tract cancers of any stage.
This may be explained by the rarity of CCA and the sparsity of evidence on the role of NAT in this type of cancer.
Nonetheless, it is the main reason for the inability to draw safe conclusions, as specific management pathways and
outcomes for the management of locally advanced dCCA cannot be derived from the literature. Most studies were of
single-centre and retrospective design and limited by small numbers, while larger retrospective studies using national
data were heterogenous and offer little insight into the pre-operative resectability definition and the indications and
specific outcomes of NAT.
Another group in which dCCAs are often reported within, as the least common subgroup[46], are peri-ampullary
malignancies, due to their similar presentation and operative management. The comparison of dCCA and PDAC is
especially important in the context of NAT, as misdiagnosis can occur due to difficulties and limitations in interpretation
of imaging and diagnostic cytology. A definitive rate of such misdiagnosis is not available in the literature, however
across 2 included studies, 4 patients with dCCA received NAT due to a misdiagnosis of PDAC[28,31].
Whilst the presented case series is limited by its single-centre nature and the small numbers reported, the clear
definition of locally advanced disease with appropriate MDT validation is rarely identified in the existing literature.
Additionally, due to the rare nature of the disease, our cohort is an important and substantial contribution to the very
limited number of reported cases of locally advanced dCCA treated with NAT.
CONCLUSION
From our own series and included studies that report on NAT for dCCA with extensive vascular involvement, evidence
for the benefit of NAT is limited. Consensus on the criteria for a uniform definition of resectability for dCCA is required,
which will provide homogeneity in reporting of pathways and outcomes. We propose the use of the already established
NCCN criteria for PDAC. Due to the rare nature of the disease and thus the difficulty in conducting randomised trials,
future studies should focus on international observational high-quality studies and prospective registries to investigate
the value and other indications for possible use of NAT, such as LN involvement or CA19-9; agents used, including
biological agents; and pathway outcomes, such as failure to progress to surgery.
FOOTNOTES
Author contributions: Chatzizacharias N conceptualized the work; Hall LA, Loader D Gouveia S, Burak M, Halle-Smith J, Labib P, and
Alarabiyat M completed data collection and analysis for the case series; Hall LA, Gouveia S, Burak M, and Halle-Smith J completed the
systematic review; Hall LA, Loader D, Halle-Smith J, and Chatzizacharias N prepared the original draft; Labib P, Alarabiyat M,
Marudanayagam R, Dasari BVM, Roberts KJ, Raza SS, Papamichail M, Bartlett DC, Sutcliffe RP, and Chatzizacharias N reviewed and
edited the manuscript; Chatzizacharias N was senior supervisor for the project; and all authors have read and approved the final version
of the manuscript.
Hall LA et al. NAT for dCCA with arterial involvement
WJGS https://www.wjgnet.com 2699 August 27, 2024 Volume 16 Issue 8
Conflict-of-interest statement: The authors have no conflicts of interest to declare.
PRISMA 2009 Checklist statement: The authors have read the PRISMA 2009 Checklist, and the manuscript was prepared and revised
according to the PRISMA 2009 Checklist and attached checklist for submission.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers.
It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to
distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the
original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Country of origin: United Kingdom
ORCID number: Lewis A Hall 0000-0002-5012-2108; Moath Alarabiyat 0000-0003-4757-053X; Ravi Marudanayagam 0000-0002-0640-3535;
Bobby V Dasari 0000-0003-2375-1141; Keith J Roberts 0000-0003-1799-9829; Syed S Raza 0000-0003-3052-7527; Robert P Sutcliffe 0000-0002-
1881-7655; Nikolaos A Chatzizacharias 0000-0002-4864-189X.
S-Editor: Chen YL
L-Editor: A
P-Editor: Cai YX
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Background: Although surgery is the mainstay of curative-intent treatment for extrahepatic biliary tract cancer (EBTC), recurrence following surgery can be high and prognosis poor. The impact of neoadjuvant therapy (NAT) relative to upfront surgery (US) among patients with EBTC remains unclear. Methods: The Surveillance, Epidemiology, and End Results (SEER) databases was utilized to identify patients who underwent surgery from 2006 to 2017 for EBTC, including gallbladder cancer (GBC) and extrahepatic cholangiocarcinoma (ECC). Trends in NAT utilization were investigated, and the impact of NAT on prognosis was compared with US using a propensity score-matched (PSM) analysis. Results: Among 6582 EBTC patients (GBC, n = 4467, ECC, n = 2215), 1.6% received NAT; the utilization of NAT for EBTC increased over time (Ptrend = 0.03). Among patients with lymph node metastasis, the lymph node ratio was lower among patients with NAT (0.18 vs. 0.40, p < 0.01). After PSM, there was no difference in overall survival (OS) and cancer-specific survival (CSS) among patients treated with NAT versus US (5-year OS: 24.0% vs. 24.6%, p = 0.14, 5-year CSS: 38.0% vs. 36.1%, p = 0.21). A subgroup analysis revealed that NAT was associated with improved OS and CSS among patients with stages III–IVA of the disease (OS: HR 0.65, 95%CI 0.46–0.92, p = 0.02, CSS: HR 0.62, 95%CI 0.41–0.92, p = 0.01). Conclusions: While NAT did not provide an overall benefit to patients undergoing surgery for EBTC, individuals with advanced-stage disease had improved OS and CSS with NAT. An individualized approach to NAT use among patients with EBTC may provide a survival benefit.
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Introduction: Data supporting the utilization of neoadjuvant chemotherapy (NAC) in patients receiving resection for cholangiocarcinoma (CCA) remains uncertain. We aimed to determine whether NAC followed by resection improves long-term survival in intrahepatic (iCCA), perihilar (hCCA), and distal (dCCA) cholangiocarcinoma, analyzed separately. Methods: Patients undergoing surgery for iCCA, hCCA, and dCCA, receiving either none, NAC, or adjuvant chemotherapy (AC) from 2010 to 2016 were identified from the National Cancer Database (NCDB). Cox regression was performed to account for selection bias and to assess the impact of surgery alone (SA) versus either NAC or AC on overall survival (OS). Results: There were 9411 patients undergoing surgery for iCCA (n = 3772, 39.5%), hCCA (n = 1879, 20%), and dCCA (n = 3760, 40%). Of these, 10.6% (n = 399), 6.5% (n = 123), and 7.2% (n = 271) with iCCA, hCCA, and dCCA received NAC, respectively. On adjusted analyses, patients receiving NAC followed by surgery had significantly improved OS, compared to SA for iCCA (HR 0.75, CI95% 0.64-0.88, p < 0.001), hCCA (HR 0.72, CI95% 0.54-0.97, p = 0.033), and for dCCA (HR 0.65, CI95% 0.53-0.78, p < 0.001). However, sensitivity analyses demonstrated no differences in OS between NACs, followed by surgery or AC after surgery in iCCA (HR 1.19, CI95% 0.99-1.45, p = 0.068), hCCA (HR 0.83 CI95% 0.59-1.19, p = 0.311), and dCCA (HR 1.13 CI95% 0.91-1.41, p = 0.264). Conclusions: This study associated NAC with increased OS for all CCA subtypes, even in patients with margin-negative and node-negative disease; however, no differences were found between NAC and AC. Our results highlight that a careful and interdisciplinary evaluation should be sought to consider NAC in CCA and warrant the need of larger studies to provide robust recommendation.
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Body composition changes during neoadjuvant therapy and their clinical significance have not been clarified. The present study aimed to investigate body composition changes during neoadjuvant chemoradiation therapy (NACRT) in patients with distal bile duct cancer and the clinical impact on postoperative complications and the prognosis. A total of 16 patients with distal bile duct cancer who underwent curative resection after NACRT were retrospectively evaluated. The area of skeletal muscle, visceral fat and subcutaneous fat on computed tomography and immunological and nutritional indices were assessed before and after NACRT. All 16 patients completed NACRT followed by pancreaticoduodenectomy without mortality. There was no significant change in the skeletal muscle mass index (SMI) during NACRT. Of the 16 patients, nine (56%) were defined as sarcopenic before NACRT, and eight (50%) met the criteria for sarcopenic after NACRT. The SMI and total fat area were significantly associated with postoperative pancreatic fistula (POPF) (P=0.019 and P=0.007, respectively). The patients with sarcopenia had a shorter disease-free survival time and overall survival time in comparison to patients without sarcopenia (P=0.025 and P=0.115, respectively). In conclusion, NACRT for distal bile duct cancer did not significantly affect the body composition, or the immunological or nutritional indices. Sarcopenia after NACRT was significantly associated with early recurrence in patients with distal bile duct cancer who received NACRT.
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Patients in the neoadjuvant FOLFIRINOX group received four neoadjuvant cycles of FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, leucovorin 400 mg/m2, and fluorouracil 400 mg/m2 bolus then 2400 mg/m2 over 46 h on day 1 of each 14-day cycle), followed by surgery and adjuvant chemotherapy. Patients in the upfront surgery group underwent surgery and then received adjuvant chemotherapy. Initially, adjuvant chemotherapy was gemcitabine plus capecitabine (gemcitabine 1000 mg/m2 over 30 min on days 1, 8, and 15 of each 28-day cycle and capecitabine 830 mg/m2 twice daily for 3 weeks with 1 week of rest in each 28-day cycle; four cycles in the neoadjuvant FOLFIRINOX group, six cycles in the upfront surgery group). A protocol amendment was subsequently made to permit use of adjuvant modified FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 150 mg/m2, leucovorin 400 mg/m2, and fluorouracil 2400 mg/m2 over 46 h on day 1 of each 14-day cycle; eight cycles in the neoadjuvant FOLFIRINOX group, 12 cycles in the upfront surgery group). Randomisation was performed with a computerised algorithm that stratified for each participating centre and used a concealed block size of two to six. Patients, investigators, and study team members were not masked to treatment allocation. The primary endpoint was overall survival at 18 months. Analyses were done in the intention-to-treat (ITT) and per-protocol populations. Safety was assessed in all patients who were randomly assigned and received at least one cycle of neoadjuvant or adjuvant therapy. This trial is registered with ClinicalTrials.gov, NCT02919787, and EudraCT, 2015-001635-21, and is ongoing. Findings: Between Feb 8, 2017, and April 21, 2021, 77 patients were randomly assigned to receive neoadjuvant FOLFIRINOX and 63 to undergo upfront surgery. All patients were included in the ITT analysis. For the per-protocol analysis, 17 (22%) patients were excluded from the neoadjuvant FOLFIRINOX group (ten did not receive neoadjuvant therapy, four did not have pancreatic ductal adenocarcinoma, and three received another neoadjuvant regimen), and eight (13%) were excluded from the upfront surgery group (seven did not have pancreatic ductal adenocarcinoma and one did not undergo surgical exploration). 61 (79%) of 77 patients in the neoadjuvant FOLFIRINOX group received neoadjuvant therapy. The proportion of patients alive at 18 months by ITT was 60% (95% CI 49–71) in the neoadjuvant FOLFIRINOX group versus 73% (62–84) in the upfront surgery group (p=0·032), and median overall survival by ITT was 25·1 months (95% CI 17·2–34·9) versus 38·5 months (27·6–not reached; hazard ratio [HR] 1·52 [95% CI 1·00–2·33], log-rank p=0·050). The proportion of patients alive at 18 months in per-protocol analysis was 57% (95% CI 46–67) in the neoadjuvant FOLFIRINOX group versus 70% (55–83) in the upfront surgery group (p=0·14), and median overall survival in per-protocol population was 23·0 months (95% CI 16·2–34·9) versus 34·4 months (19·4–not reached; HR 1·46 [95% CI 0·99–2·17], log-rank p=0·058). In the safety population, 42 (58%) of 73 patients in the neoadjuvant FOLFIRINOX group and 19 (40%) of 47 patients in the upfront surgery group had at least one grade 3 or worse adverse event. 63 (82%) of 77 patients in the neoadjuvant group and 56 (89%) of 63 patients in the upfront surgery group had resection (p=0·24). One sudden death of unknown cause and one COVID-19-related death occurred after the first cycle of neoadjuvant FOLFIRINOX. Adjuvant chemotherapy was initiated in 51 (86%) of 59 patients with resected pancreatic ductal adenocarcinoma in the neoadjuvant FOLFIRINOX group and 44 (90%) of 49 patients with resected pancreatic ductal adenocarcinoma in the upfront surgery group (p=0·56). Adjuvant modified FOLFIRINOX was given to 13 (25%) patients in the neoadjuvant FOLFIRINOX group and 19 (43%) patients in the upfront surgery group. During adjuvant chemotherapy, neutropenia (11 [22%] patients in the neoadjuvant FOLFIRINOX group and five [11%] in the upfront surgery group) was the most common grade 3 or worse adverse event. Interpretation: This phase 2 trial did not show a survival benefit from neoadjuvant FOLFIRINOX in resectable pancreatic ductal adenocarcinoma compared with upfront surgery. Implementation of neoadjuvant FOLFIRINOX was challenging. Future trials on treatment sequencing in resectable pancreatic ductal adenocarcinoma should be biomarker driven.
Article
Background: Biliary tract cancers, which arise from the intrahepatic or extrahepatic bile ducts and the gallbladder, generally have a poor prognosis and are rising in incidence worldwide. The standard-of-care treatment for advanced biliary tract cancer is chemotherapy with gemcitabine and cisplatin. Because most biliary tract cancers have an immune-suppressed microenvironment, immune checkpoint inhibitor monotherapy is associated with a low objective response rate. We aimed to assess whether adding the immune checkpoint inhibitor pembrolizumab to gemcitabine and cisplatin would improve outcomes compared with gemcitabine and cisplatin alone in patients with advanced biliary tract cancer. Methods: KEYNOTE-966 was a randomised, double-blind, placebo-controlled, phase 3 trial done at 175 medical centres globally. Eligible participants were aged 18 years or older; had previously untreated, unresectable, locally advanced or metastatic biliary tract cancer; had disease measurable per Response Evaluation Criteria in Solid Tumours version 1.1; and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Eligible participants were randomly assigned (1:1) to pembrolizumab 200 mg or placebo, both administered intravenously every 3 weeks (maximum 35 cycles), in combination with gemcitabine (1000 mg/m2 intravenously on days 1 and 8 every 3 weeks; no maximum duration) and cisplatin (25 mg/m2 intravenously on days 1 and 8 every 3 weeks; maximum 8 cycles). Randomisation was done using a central interactive voice-response system and stratified by geographical region, disease stage, and site of origin in block sizes of four. The primary endpoint of overall survival was evaluated in the intention-to-treat population. The secondary endpoint of safety was evaluated in the as-treated population. This study is registered at ClinicalTrials.gov, NCT04003636. Findings: Between Oct 4, 2019, and June 8, 2021, 1564 patients were screened for eligibility, 1069 of whom were randomly assigned to pembrolizumab plus gemcitabine and cisplatin (pembrolizumab group; n=533) or placebo plus gemcitabine and cisplatin (placebo group; n=536). Median study follow-up at final analysis was 25·6 months (IQR 21·7-30·4). Median overall survival was 12·7 months (95% CI 11·5-13·6) in the pembrolizumab group versus 10·9 months (9·9-11·6) in the placebo group (hazard ratio 0·83 [95% CI 0·72-0·95]; one-sided p=0·0034 [significance threshold, p=0·0200]). In the as-treated population, the maximum adverse event grade was 3 to 4 in 420 (79%) of 529 participants in the pembrolizumab group and 400 (75%) of 534 in the placebo group; 369 (70%) participants in the pembrolizumab group and 367 (69%) in the placebo group had treatment-related adverse events with a maximum grade of 3 to 4. 31 (6%) participants in the pembrolizumab group and 49 (9%) in the placebo group died due to adverse events, including eight (2%) in the pembrolizumab group and three (1%) in the placebo group who died due to treatment-related adverse events. Interpretation: Based on a statistically significant, clinically meaningful improvement in overall survival compared with gemcitabine and cisplatin without any new safety signals, pembrolizumab plus gemcitabine and cisplatin could be a new treatment option for patients with previously untreated metastatic or unresectable biliary tract cancer. Funding: Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA.
Article
Background This study was conducted to evaluate the clinical feasibility of nab-paclitaxel plus gemcitabine-cisplatin triplet chemotherapy in patients with locally advanced cholangiocarcinoma in real-world practice. Methods We retrospectively reviewed patients with locally advanced cholangiocarcinoma who were treated with nab-paclitaxel plus gemcitabine-cisplatin between October 2019 and August 2021 at a single institution. The initial diagnosis of cholangiocarcinoma was histologically confirmed. Results One hundred twenty-nine patients were included in this study. Among the patients with a measurable lesion (57.4%), the objective response rate and disease control were 60.8% and 91.9%, respectively. Seventy-seven patients (59.7%) were determined as resectable after triplet chemotherapy, but 73 (56.6%) underwent subsequent curative surgery. The major postoperative complication rate was 15.1%, and there were 2 postoperative mortalities (2.7%). There were 6 complete remission cases (8.2%) in the final pathology. The R0 resection was achieved in 67 patients (91.8%). Despite the initial locally advanced cholangiocarcinoma, a pathologic T stage of less than T2 was reported in 67 patients (91.8%). Fifty-two patients (71.2%) had no lymph node metastasis. Patients who underwent surgery after triplet chemotherapy had significantly higher 12-month overall survival (95.9% vs 76.8%; P < .001) than those treated with chemotherapy alone. Conclusion Nab-paclitaxel plus gemcitabine-cisplatin chemotherapy demonstrated a down-staging effect through a high response rate, indicating that this triplet chemotherapy is feasible as induction therapy in patients with locally advanced cholangiocarcinoma.
Article
Background and objectives: Evidence for neoadjuvant therapy (NAT) in extrahepatic cholangiocarcinoma (eCCA) is limited. Our objectives were to: (1) characterize treatment trends, (2) identify factors associated with receipt of NAT, and (3) evaluate associations between NAT and postoperative outcomes. Methods: Retrospective cohort study of the National Cancer Database (2004-2017). Multivariable logistic regression assessed associations between NAT and postoperative outcomes. Stratified analysis evaluated differences between surgery first, neoadjuvant chemotherapy, and neoadjuvant chemoradiation (CRT). Results: Among 8040 patients, 417 (5.2%) received NAT. NAT increased during the study period 2.9%-8.4% (p < 0.001). Factors associated with receipt of NAT included age <50 (vs. >75, odds ratio [OR] 4.32, p < 0.001) and stage 3 disease (vs. 1, OR 1.68, p = 0.01). Compared with surgery first, patients who received NAT had higher odds of R0 resection (OR 1.49, p = 0.01) and lower 30-day mortality (OR 0.51, p = 0.04). On stratified analysis, neoadjuvant chemotherapy was not associated with differences in any outcomes. However, neoadjuvant CRT was associated with improvement in R0 resection (OR 3.52, <0.001) and median survival (47.8 vs. 25.3 months, log-rank < 0.001) compared to surgery first. Conclusions: NAT, particularly neoadjuvant CRT, was associated with improved postoperative outcomes. These data suggest expanding the use of neoadjuvant CRT for eCCA.
Article
Background: In contrast to pancreatic ductal adenocarcinoma (PDAC), neoadjuvant therapy (NAT) for periampullary adenocarcinomas is not well studied, with data limited to single-institution retrospective reviews with small cohorts. We sought to compare outcomes of NAT versus upfront resection (UR) for non-PDAC periampullary adenocarcinomas. Patients and methods: Using the National Cancer Database (NCDB), we identified patients who underwent surgery for extrahepatic cholangiocarcinoma, ampullary adenocarcinoma, or duodenal adenocarcinoma from 2006 to 2016. We compared outcomes between NAT versus UR groups for each tumor subtype with 1:3 propensity score matching. Cox regression was used to identify predictors of survival. Results: Among 7656 patients who underwent resection for non-PDAC periampullary adenocarcinoma, the proportion of patients who received NAT increased from 6 to 11% for cholangiocarcinoma (p < 0.01), 1 to 4% for ampullary adenocarcinoma (p = 0.01), and 5 to 8% for duodenal adenocarcinoma (p = 0.08). Length of stay, readmission, and 30-day mortality were comparable between NAT and UR. All tumor subtypes were downstaged following NAT (p < 0.01). The R0 resection rate was significantly higher in patients with extrahepatic cholangiocarcinoma who received NAT, and these patients had improved median overall survival (38 vs 26 months, p < 0.001). After adjustment for clinicopathologic factors and adjuvant chemotherapy, use of NAT was associated with improved survival in patients with cholangiocarcinoma [hazard ratio (HR) 0.69, 95% confidence interval (CI) 0.54-0.89, p = 0.004] but not duodenal or ampullary adenocarcinoma. The survival advantage for cholangiocarcinoma persisted after propensity matching. Conclusion: This national cohort analysis suggests, for the first time, that neoadjuvant therapy is associated with improved survival in patients with extrahepatic cholangiocarcinoma.
Article
Background & Aims Cholangiocarcinoma (CCA) is a rare and heterogeneous biliary cancer, whose incidence and related mortality is increasing. This study investigates the clinical course of CCA and subtypes (intrahepatic [iCCA], perihilar [pCCA], and distal [dCCA]) in a pan-European cohort. Methods The ENSCCA Registry is a multicenter observational study. Patients were included if they had a histologically proven diagnosis of CCA between 2010-2019. Demographic, histomorphological, biochemical, and clinical studies were performed. Results Overall, 2,234 patients were enrolled (male/female=1.29). iCCA (n = 1,243) was associated with overweight/obesity and chronic liver diseases involving cirrhosis and/or viral hepatitis; pCCA (n = 592) with primary sclerosing cholangitis; and dCCA (n = 399) with choledocholithiasis. At diagnosis, 42.2% of patients had local disease, 29.4% locally advanced disease (LAD), and 28.4% metastatic disease (MD). Serum CEA and CA19-9 showed low diagnostic sensitivity, but their concomitant elevation was associated with increased risk of presenting with LAD (odds ratio 2.16; 95% CI 1.43-3.27) or MD (odds ratio 5.88; 95% CI 3.69-9.25). Patients undergoing resection (50.3%) had the best outcomes, particularly with negative-resection margin (R0) (median overall survival [mOS] = 45.1 months); however, margin involvement (R1) (hazard ratio 1.92; 95% CI 1.53-2.41; mOS = 24.7 months) and lymph node invasion (hazard ratio 2.13; 95% CI 1.55-2.94; mOS = 23.3 months) compromised prognosis. Among patients with unresectable disease (49.6%), the mOS was 10.6 months for those receiving active palliative therapies, mostly chemotherapy (26.2%), and 4.0 months for those receiving best supportive care (20.6%). iCCAs were associated with worse outcomes than p/dCCAs. ECOG performance status, MD and CA19-9 were independent prognostic factors. Conclusion CCA is frequently diagnosed at an advanced stage, a proportion of patients fail to receive cancer-specific therapies, and prognosis remains dismal. Identification of preventable risk factors and implementation of surveillance in high-risk populations are required to decrease cancer-related mortality. Lay summary This is, to date, the largest international (pan-European: 26 hospitals and 11 countries) observational study, in which the course of cholangiocarcinoma has been investigated, comparing the 3 subtypes based on the latest International Classification of Diseases 11th Edition (ICD-11) (i.e., intrahepatic [2C12], perihilar [2C18], or distal [2C15] affected bile ducts), which come into effect in 2022. General and tumor-type specific features at diagnosis, risk factors, biomarker accuracy, as well as patient management and outcomes, are presented and compared, outlining the current clinical state of cholangiocarcinoma in Europe.