Gastrointest Tumors 2014;1:41–52

DOI: 10.1159/000354992 © 2013 S. Karger AG, Basel

Published online: September 12, 2013 2296–3774/13/0011–0041$38.00/0
www.karger.com/gat

Mini-Review

Pancreatic Cancer: Current Options

for Diagnosis, Staging and Therapeutic
Management
Werner Hartwig Markus W. Büchler
Department of General, Visceral and Transplantation Surgery, University of Heidelberg,
Heidelberg, Germany

Key Message
An interdisciplinary, multimodal approach to therapy is critical for improving the out-
comes of patients with pancreatic cancer.

Practical Implications
Cross-sectional imaging techniques (such as contrast-enhanced multidetector computed
tomography) are useful for assessing tumor resectability. For localized, non-metastatic,
resectable tumors, the necessity of preoperative biopsies remains controversial. Important
prognostic parameters are tumor size, invasion of surrounding tissue, lymph node metas-
tasis and distant metastasis. Various classification systems based on the TNM system
have been used for tumor staging and prognosis. The presence of distant metastases is
regarded as non-resectable disease, requiring chemotherapy as first treatment. The defi-
nition of borderline resectable tumors is still under debate, although a recent definition
has been provided by an expert consensus statement. Standard lymphadenectomy is the
recommended procedure in pancreatoduodenectomy, based upon the guidelines of
the International Study Group of Pancreatic Surgery (ISGPS). Adjuvant chemotherapy is
applied in generally all cases of pancreatic ductal adenocarcinoma following macro-
scopic complete tumor resection. The benefits of adjuvant chemoradiotherapy or immu-
nochemoradiotherapy, or neoadjuvant therapy, however, remain a matter of contro-
versy. For palliative treatment gemcitabine monotherapy is widely used; the FOLFIRINOX
protocol provides an alternative for a minority of patients.

Markus W. Büchler, MD
Department of General, Visceral and Transplantation Surgery
University of Heidelberg
Im Neuenheimer Feld 110, DE–69120 Heidelberg (Germany)
E-Mail markus.buechler @ med.uni-heidelberg.de
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DOI: 10.1159/000354992 © 2013 S. Karger AG, Basel
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Hartwig et al.: Pancreatic Cancer: Current Options for Diagnosis, Staging and
Therapeutic Management

Key Words
Diagnostics · Multimodal therapy · Palliative therapy · Pancreatic ductal adenocarcinoma ·
Surgery

Abstract
Background: Pancreatic cancer is characterized by frequently delayed diagnosis and aggres-
sive tumor growth which hampers most of the current treatment modalities. This review aims
to summarize the available evidence about the diagnostic and therapeutic aspects of resect-
able and non-resectable pancreatic cancer therapy. Summary: Embedded in the concept of
multimodal therapy, surgery plays the central role in the treatment of pancreatic cancer. With
advantageous tumor characteristics and complete tumor resection as the most relevant pos-
itive prognostic factors, the detection of premalignant or early invasive lesions combined with
safe and oncologic adequate surgery is the major therapeutic aim. Most pancreatic adeno-
carcinomas are locally advanced or metastatic when diagnosed and need to be treated by the
combination of surgery and (radio)chemotherapy or by palliative chemotherapy.
© 2013 S. Karger AG, Basel

Introduction

Despite recent advances in cancer therapy, pancreatic ductal adenocarcinoma remains

one of the most aggressive tumor entities and is among the most frequent causes of tumor-
associated deaths in the European Union and the United States [1, 2]. Whereas the overall
5-year survival rate is around 5%, surgery is the only potential hope of a cure. The 5-year
survival increases to >20% in resected patients who undergo multimodal therapy [3, 4].
Whilst pancreatic surgery has developed and become a relatively safe intervention in
specialized centers, complete tumor resection combined with advantageous tumor charac-
teristics have been demonstrated to be the most critical parameters to achieve long-term
survival [5–7].
Current guidelines differentiate between resectable, borderline resectable, locally ad-
vanced unresectable and metastatic pancreatic cancer [8]. Surgery embedded in a multimod-
al setting is the cornerstone in the therapy of resectable and borderline resectable dis-
ease. Although limited comparative data are available, there is some evidence from smaller
randomized controlled trials that resection of locally invasive pancreatic cancer, which
included American Joint Committee of Cancer (AJCC)/International Union Against Cancer
(UICC) stage IIA and IIB tumors or those invading the porto-mesenteric vein, results in longer
survival compared to chemoradiation [9] or palliative gastrobiliary bypass [10]. Early diag-
nosis of pancreatic cancer combined with correct tumor staging is of utmost importance to
apply the adequate multimodal tumor therapy. The present review summarizes the current
evidence on the diagnostics, staging and therapy of pancreatic cancer and highlights some
areas of remaining controversy. Some parts of the present review have been published previ-
ously by the authors, where a more detailed analysis of possible improvements of surgical
results for pancreatic cancer and of the therapy of advanced-stage disease is provided [11, 12].

Diagnostics

Imaging
Small tumor size is one of the most relevant positive predictive factors in pancreatic
cancer, and high-quality imaging techniques play a crucial role in the diagnosis of pancreatic
tumors. In most cases, tumor diagnosis and resectability is adequately evaluable using one
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Hartwig et al.: Pancreatic Cancer: Current Options for Diagnosis, Staging and
Therapeutic Management

cross-sectional imaging study and the current state-of-the-art imaging modality is contrast-
enhanced multidetector computed tomography (CT) with advanced volumetric processing
techniques [8, 13]. Patients are typically scanned in an arterial and venous phase. The arterial
phase shows excellent opacification of the celiac axis and the superior mesenteric artery,
whereas the superior mesenteric vein, the portal vein, the splenic vein, and the pancreas itself
are well opacified in the venous phase. Likewise, the detection of liver metastasis is optimal in
the latter phase. The method of choice in the imaging of pancreatic pathologies is hydro-CT,
which involves distension of the stomach and duodenum by administration of 1–1.5 l of water
as a negative contrast medium under medically induced hypotension by administration of
Buscopan. Magnetic resonance imaging including magnetic resonance cholangiography may
be advantageous for the differentiation of cystic pancreatic neoplasms, but does not add infor-
mation on resectability. Endoscopic ultrasound (EUS) can complement other imaging modal-
ities with valuable staging information and is good in detecting especially smaller lesions. At
present, the routine use of endoscopic retrograde cholangiopancreatography or fluorine-18
fluorodeoxyglucose positron emission tomography cannot be recommended [8, 13].

Tumor Biopsy
In potentially resectable tumors, the necessity for preoperative biopsy of suspected
pancreatic cancer is controversial. Positions vary between mandatory histological proof of
carcinoma prior to surgical intervention to prevent unnecessary operations and to decrease
health care costs [14–16] and the indication of operative exploration even on minor suspicion
of malignancy to minimize delay of surgery and to prevent tumor spread by biopsy proce-
dures [17–20]. Unlike resectable tumors, histopathologic confirmation is necessary in patients
deemed to have inoperable tumors or those who are medically unsuitable for surgery. In the
National Comprehensive Cancer Network (NCCN) guidelines for pancreatic adenocarcinoma,
it is strongly recommended that all patients with unresectable pancreatic cancer have cancer
confirmation prior to non-surgical treatment [21]. In general, extrapancreatic metastasis
should be preferentially targeted by biopsy in case of verified systemic disease, due to easier
accessibility, higher cell retrieval and a presumably lower or comparable complication rate
[22, 23]. EUS-guided fine needle aspiration (EUS-FNA) is regarded to be the best modality for
obtaining a tissue diagnosis in locoregional disease when needed (e.g. prior to neoadjuvant
therapy) [8, 13].
Recent meta-analyses demonstrated a pooled sensitivity of EUS-FNA in diagnosing the
correct etiology for solid pancreatic mass of 86.8% and a pooled specificity of 95.8% [24]. The
sensitivity was higher when a 25 G needle system was used as compared to a 22 G needle
system [25]. For cystic lesions, FNA accuracy data are much worse. A pooled sensitivity of
54% was described for cytology and of 63% for cyst fluid carcinoembryonic antigen [26].
Based on these data, preoperative biopsy cannot be recommended in patients with a curative
resectable pancreatic neoplasm. The inaccuracy and high rate of false-negative results of
biopsies, the risk of biopsy-induced complications with tumor seeding or delay of surgery,
and the lack of evidence that a preoperative biopsy can alter management should discourage
the physician from performing preoperative biopsies on these patients [27].

Tumor Staging

TNM Staging
The TNM classification is used to characterize the local and systemic growth of pancreatic
adenocarcinoma. Tumor size and invasion of nearby tissue, lymph node metastasis, and
distant metastases have been shown to correlate with the prognosis of the disease. The UICC
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Hartwig et al.: Pancreatic Cancer: Current Options for Diagnosis, Staging and
Therapeutic Management

Table 1. TNM staging of pancreatic adenocarcinoma

TNM classification

T = primary tumor
TX primary tumor cannot be assessed
T0 no evidence of primary tumor
Tis carcinoma in situ
T1 tumor restricted to the pancreas, ≤2 cm in greatest dimension
T2 tumor restricted to the pancreas, >2 cm in greatest dimension
T3 tumor extends beyond the pancreas, no involvement of the celiac axis or superior mesenteric artery
T4 tumor affects the celiac axis or the superior mesenteric artery
N = regional lymph node
NX regional lymph nodes cannot be assessed
N0 no regional lymph node metastasis
N1 regional lymph node metastasis
M = distant metastasis
M0 no distant metastasis
M1 distant metastasis

UICC staging and survival

Stages Resectability Median 5-year
survival, survival,
months %

0 (Tis, N0, M0) carcinoma in situ, resectable NA NA

IA (T1, N0, M0) localized, resectable 24 – 42 31 – 39
IB (T2, N0, M0) localized, resectable 20 – 26 22 – 27
IIA (T3, N0, M0) locally invasive, resectable, eventually borderline 15 – 30 16 – 25
resectable when extended T3
IIB (T1 – 3, N1, M0) locally invasive, resectable, eventually borderline 12 – 21 8 – 10
resectable when extended T3
III (T4, any N, M0) locally advanced, borderline resectable or unresectable 11 – 14 0–7
IV (any T, any N, M1) distant metastasis, palliative 5 – 12 0–4

Survival data for resected pancreatic adenocarcinoma extracted from [5, 60 – 62]. NA = Data not available.
Table as published by Hartwig et al. [11].

and the AJCC have released a staging system which is based on the TNM classification, with
the aim to characterize tumor stages that have a distinguishable prognosis [28, 29]. Table 1
describes the TNM classification and the AJCC/UICC staging system for pancreatic cancer and
provides an overview of published stage-specific median survival times and 5-year survival
rates. Further prognostic parameters that are not included in the AJCC/UICC staging system
include the grade of differentiation of tumor cells, tumor clearance at operative resection
margins and perineural or lymphovascular invasion. Since a large variation of the prognosis
of patients within the AJCC/UICC tumor stages has been described, prognostic scores and
nomograms have been suggested with possible effects on peri- and postoperative decision
making [5, 30].

Tumor Markers
Tumor marker-adjusted surgical as well as non-surgical therapy in pancreatic cancer has
been proposed by several authors. At present, CA19-9 may qualify best for this purpose due
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Therapeutic Management

to its secretion in about 75–80% of pancreatic cancer patients. Other tumor markers have
failed to be successfully implemented in the clinical routine of pancreatic cancer therapy. Pre-
as well as postresection CA19-9 levels have been demonstrated to contribute valuable infor-
mation in the prediction of malignancy, resectability and prognosis of pancreatic cancer
patients. Resectability and survival rates progressively decrease with increasing CA19-9
levels, with a dismal prognosis in patients with preoperative CA19-9 levels ≥1,000 U/ml or
early postoperative increasing levels [31–33]. However, at present it is unclear whether
extraordinarily increased CA19-9 indicates otherwise undetected disseminated disease
which needs profound diagnostic work-up, or whether neoadjuvant therapy may help identify
those patients who might not benefit from radical resection [34]. Likewise, persistently high
or increasing postresection CA19-9 levels may select patients who might not benefit from
standard adjuvant therapy [32].

Surgery

Apart from favorable tumor characteristics, complete tumor resection is probably the
most relevant prognostic factor in patients with pancreatic cancer. Evidence from randomized,
controlled trials investigating surgical vs. non-surgical therapy is limited because studies on
this issue are considerably hampered by ethical concerns. However, a multicenter trial
comparing resection and chemoradiotherapy for locally invasive resectable pancreatic cancer
(AJCC/UICC stages IIA and IIB) demonstrated significantly better outcomes in the surgery
group, despite the premature termination of the trial [9]. Likewise, a small randomized study
demonstrated longer survival with mono-bloc spleno-pancreatoduodenectomy compared to
palliative gastrobiliary bypass in patients with advanced pancreatic cancer and portal-mesen-
teric venous invasion [10]. The extension of the surgical intervention for pancreatic adeno-
carcinoma has been a matter of intense controversy. Some of these issues are highlighted in
the following sections.

Resectability
There is wide agreement that localized, non-metastatic pancreatic tumors without
involvement of the porto-mesenteric vein and the main visceral arteries (AJCC/UICC tumor
stages I and II) are primarily considered resectable (table 1) [8, 13]. On the contrary, the
presence of distant metastases (AJCC/UICC tumor stage IV) is regarded to indicate non-
resectable disease and requires chemotherapy as first treatment. Circumferential encasement
of the celiac axis, the hepatic artery or the superior mesenteric artery with suspected arterial
tumor infiltration (T4 or AJCC/UICC tumor stage III) is also categorized as non-resectable in
most cases [8, 13]. At present, a wide range of definitions is available regarding borderline
resectable tumors, and a recent expert consensus statement has undertaken the effort to
provide a generally acceptable definition (table 2) [13]. However, with growing experience
in vascular surgery, pancreatic surgeons less frequently consider vascular involvement as a
criterion for non-resectability (fig. 1). In particular, involvement of the superior mesenteric
or portal vein, even in cases with circumferential encasement or occlusion, allows for primary
resection and reconstruction by end-to-end anastomosis in most cases in experienced centers
as long as a suitable vessel proximal and distal to the area of vessel involvement is present
[35, 36].

Lymphadenectomy
Multiple studies including a large, population-based analysis have verified the negative
predictive value of lymph node involvement in pancreatic cancer [37]. Both the number of
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&
#

%
*
§

Fig. 1. Intraoperative finding after resection of a borderline resectable pancreatic body tumor. Total pancre-
atectomy including resection of the transverse mesocolon and extensive dissection of the soft tissue around
the superior mesenteric artery and the celiac trunk has been performed. Surgical site prior to reconstruction
with hepaticojejunostomy and gastrojejunostomy. # = Common hepatic artery; § = superior mesenteric ar-
tery; & = left gastric artery; * = porto-mesenteric vein after segmental resection and end-to-end anastomosis;
% = bulldog clamp on the bile duct for temporary occlusion.

Table 2. Resectable and borderline resectable pancreatic cancer according to the consensus statement of
the AHPBA/SSO/SSAT [13]

Tumors considered localized and resectable should demonstrate the following:

a No distant metastasis
b No radiographic evidence of SMV and portal vein abutment, distortion, tumor thrombus or venous en-
casement
c Clear fat planes around the celiac axis, hepatic artery and SMV
Tumors considered borderline resectable include the following:
a No distant metastasis
b Venous involvement of the SMV/portal vein demonstrating tumor abutment with or without impingement
and narrowing of the lumen, encasement of the SMV/portal vein but without encasement of the nearby
arteries, or short segment venous occlusion resulting from either tumor thrombus or encasement but
with suitable vessel proximal and distal to the area of vessel involvement, allowing for safe resection and
reconstruction
c Gastroduodenal artery encasement up to the hepatic artery with either short segment encasement or
direct abutment of the hepatic artery, without extension to the celiac axis
d Tumor abutment of the superior mesenteric artery not to exceed 180° of the circumference of the vessel
wall

AHPBA = American Hepato-Pancreato-Biliary Association; SSO = Society of Surgical Oncology; SSAT =

Society for Surgery of the Alimentary Tract; SMV = superior mesenteric vein.

lymph nodes evaluated in N0 disease and the lymph node ratio in N1 disease were among the
most powerful factors associated with survival. With the aim to improve survival, extended
lymphadenectomy including retroperitoneal soft tissue clearance has been evaluated in
various comparative studies and in four randomized controlled trials. Recent meta-analyses
[38, 39] did not support the benefit of extended lymphadenectomy on overall survival, but
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instead demonstrated a tendency towards higher rates of delayed gastric emptying. Therefore,
standard but not extended lymphadenectomy should be regarded as the procedure of choice
in pancreatoduodenectomy. A recent consensus definition of the International Study Group
of Pancreatic Surgery (ISGPS) provides a current recommendation for the lymph node stations
which should be included in standard lymphadenectomy for both pancreatic head resections
and distal pancreatectomies [40].

Vascular and Multivisceral Resections

Pancreatic head and body tumors grow in close proximity to the main visceral vessels,
and infiltration of the porto-mesenteric vein and the superior mesenteric artery or the celiac
axis is a common clinical finding in locally advanced tumors. Whereas venous infiltration is
included within the T3 category according to the TNM grading system, mesenteric artery or
celiac axis infiltration is graded a prognostic unfavorable T4 or AJCC/UICC tumor stage III
and is in general deemed to be unresectable based on surgical complexity along with poor
long-term survival (table 1). Likewise, splenic artery infiltration has been associated with
poor survival in pancreatic body and tail cancer. A recent meta-analysis of predominantly
retrospective cohort studies confirmed that arterial resection in patients undergoing pancre-
atectomy was associated with substantial morbidity and mortality and a poor long-term
survival rate which, however, was more favorable compared to patients who did not undergo
resection for locally advanced pancreatic cancer [41]. Unlike arterial resection, which at
present cannot in general be recommended, porto-mesenteric vein resection is a standard
procedure at high-volume pancreatic centers. With no randomized controlled trials avail-
able, two recent meta-analyses comprising 1,458 and 2,247 patients with pancreatoduode-
nectomy and pancreatectomy, respectively showed no differences in morbidity, mortality or
5-year overall survival between patients with venous resection and those without [35, 36].
These data affirm that experience in vascular surgery is indispensable for a pancreatic
surgeon. For locally advanced tumors, multivisceral resections are also very feasible at
specialized centers [42, 43]. Long-term results seem comparable to matched standard
pancreatectomies, but increased perioperative morbidity demands close postoperative
surveillance of patients.

Multimodal Therapy

Adjuvant Therapy
Pancreatic cancer is characterized by a high metastatic potential with possibly systemic
dissemination early in the course of the disease. Minimal residual disease after pancreatic
resection is the rationale for adjuvant therapy. Adjuvant therapy has advanced to such an
extent that it now plays an inherent role in pancreatic cancer treatment. The European Study
Group of Pancreatic Cancer (ESPAC) was the first to report significantly increased median and
5-year survival rates with adjuvant fluorouracil plus folinic acid after R0/R1 resection
compared to surgery alone [44]. This survival benefit was further supported by the composite
data from the ESPAC-1 and ESPAC-3 trials [45]. More recently, the CONKO-001 and Asian
JSAP-02 trials that evaluated adjuvant gemcitabine vs. observation confirmed a significant
increase in disease-free survival, median survival and estimated 5-year overall survival
compared to surgery alone [4, 46, 47]. The comparison of adjuvant fluorouracil plus folinic
acid vs. gemcitabine did not show any survival differences, but significantly less treatment-
related serious adverse events with gemcitabine were observed [3]. Similar to pancreatic
ductal adenocarcinoma, adjuvant therapy was also effective in resected periampullary adeno-
carcinomas when multivariate analysis adjusted for prognostic variables [48]. Overall, the
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available evidence from randomized controlled trials clearly shows an improvement of

surgical results when adjuvant chemotherapy is added.
Unlike chemotherapy, the benefit of adjuvant chemoradiotherapy or immunochemo-
radiotherapy in pancreatic cancer remains controversial despite its wide-range use in the
United States. Meta-analyses of randomized controlled trials could not identify an overall
beneficial effect of adjuvant chemoradiotherapy [49, 50]. Conflicting results were found in the
subgroup of patents with R1 resections [49, 50]. Similarly, chemoradiotherapy proved more
toxic and less effective in locally advanced unresectable pancreatic cancer compared to
gemcitabine alone [51]. A recent randomized controlled phase III trial of adjuvant chemora-
diotherapy plus interferon α showed similar survival rates but an enormously increased rate
of grade 3 or 4 toxicity (85% of patients) compared to fluorouracil and folinic acid [52].
However, the median survival times of 26.5 and 28.5 months, which are the highest reported
for resected pancreatic adenocarcinoma in a randomized controlled setting to date, reflect
the promising results which can be achieved by surgery with rather aggressive soft tissue
clearance as performed in most patients in that study.

Neoadjuvant Therapy
The role of neoadjuvant therapy in pancreatic cancer is less well understood, and evidence
supporting its benefit originates from phase I/II trials and retrospective analyses. The
rationale for neoadjuvant therapy is two-fold. First, locally non-resectable or borderline
resectable tumors which infiltrate the superior mesenteric artery and/or the celiac trunk or
the porto-mesenteric vein may be downstaged with the aim to make subsequent resection
possible. With this intent, irradiation of the local tumor site is the main element of neoad-
juvant therapy in order to achieve tumor shrinkage. Second, occult metastatic disease at the
time of primary diagnosis may be adequately treated by the chemotherapeutic component of
neoadjuvant therapy. By separating progressive from non-progressive disease, neoadjuvant
therapy may help identify those patients with favorable tumor biology who may benefit most
from resection. Patients with poor tumor biology and disease progression are selected,
thereby the morbidity of an unnecessary surgical intervention is avoided.
Systematic reviews and meta-analyses have demonstrated that about a third of tumors
initially designated unresectable were resectable after neoadjuvant chemoradiotherapy,
with a reduced risk of positive resection margins [53]. There may be a higher risk of periop-
erative mortality in patients receiving neoadjuvant chemoradiotherapy, but no detrimental
effects on the overall survival rate, which is comparable with that of patients who were
primarily staged as resectable. However, the quality of currently available data is poor and
influenced by patient selection bias, and it is unclear which patients will benefit from neoad-
juvant chemoradiotherapy. It is obvious that responders may have a chance of cure after
complete resection. In the group of primarily resectable patients, resection and survival rates
after neoadjuvant therapy are similar to the ones observed in primarily resected tumors that
are treated by adjuvant therapy [53]. Neoadjuvant chemoradiotherapy, which is associated
with relevant grade 3–4 toxicity, cannot be considered as standard in primarily resectable
patients [8].
The lack of a widely accepted definition of unresectability or borderline resectability is
the most significant problem for studies and meta-analyses of neoadjuvant therapy in local-
ly advanced disease. Phase III trials on patients with well-defined locally unresectable or
borderline resectable tumors and applying state-of-the-art chemoradiotherapy regimens,
possibly consisting of induction chemotherapy and subsequent chemoradiotherapy, are
badly needed. The value of neoadjuvant FOLFIRINOX, which is increasingly used after it has
proved highly effective in the palliative setting [54], remains to be investigated in controlled
trials.
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Palliative Therapy

Palliative chemotherapy is the standard treatment of choice for patients with metastatic
pancreatic cancer or for those with locally advanced disease who do not qualify for surgery.
As compared to 5-fluorouracil, a modest survival benefit combined with a relevant clinical
benefit regarding pain control and Karnofsky performance status have made gemcitabine
monotherapy the therapeutic standard for years [55]. Subsequently, meta-analyses and
randomized controlled trials have demonstrated a small survival benefit for the combination
of gemcitabine with platinum derivates, capecitabine, or the tyrosine kinase inhibitor er-
lotinib [56–58]. More recently, the combination chemotherapy FOLFIRINOX showed a mar-
kedly increased response rate and overall survival compared to gemcitabine monother-
apy [54]. Despite an increase in severe adverse effects, a detailed analysis showed that the
FOLFIRINOX therapy significantly reduced quality of life impairment [59]. However, the
FOLFIRINOX protocol is only a treatment option for a minority of patients who are charac-
terized by good performance status, relatively low bilirubin levels, good bone marrow and
renal function, and without a history of significant heart disease. Surgical interventions (e.g.
bypass procedures) play a minor role in the palliative setting [12].

Disclosure Statement

The authors declare that there are no conflicts of interest.

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