# Controversies in the Management of Borderline Resectable Proximal Pancreatic Adenocarcinoma with Vascular Involvement

Authors: Olga N. Tucker; Mohamed Rela
Journal: HPB Surgery
 (2008)

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## Abstract

Synchronous major vessel resection during pancreaticoduodenectomy (PD) for borderline resectable pancreatic adenocarcinoma remains controversial. In the 1970s, regional pancreatectomy advocated by Fortner was associated with unacceptably high morbidity and mortality rates, with no impact on long-term survival.
With the establishment of a multidisciplinary approach, improvements in preoperative staging techniques, surgical expertise, and perioperative care reduced mortality rates and improved 5-year-survival rates are now achieved following resection in high-volume centres. Perioperative morbidity and mortality following PD with portal vein resection are comparable to standard PD, with reported 5-year-survival rates of up to 17%. Segmental resection and reconstruction of the common hepatic artery/proper hepatic artery (CHA/PHA) can be performed to achieve an R0 resection in selected patients with limited involvement of the CHA/PHA at the origin of the gastroduodenal artery (GDA). PD with concomitant major vessel resection for borderline resectable tumours should be performed when a margin-negative resection is anticipated at high-volume centres with expertise in complex pancreatic surgery. Where an incomplete (R1 or R2) resection is likely neoadjuvant treatment with systemic chemotherapy followed by chemoradiation as part of a clinical trial should be offered to all patients.


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## Body

## 1. Introduction

Patients with pancreatic malignancy continue to have a dismal prognosis determined by
the histological classification and extent of disease at the time of diagnosis [1]. The prognosis for histologically proven invasive pancreatic
cancer is poor, with a 5-year-survival rate of 9.7% following resection, and overall
median survival time of 8.6 months [1]. Invasive
ductal adenocarcinoma is the most common epithelial tumour of the exocrine
pancreas, of which tubular adenocarcinoma is the most common histological
subtype [1]. The only potentially curative
treatment for invasive ductal adenocarcinoma is surgical resection. However,
only 10–20% of patients
are candidates for resection as approximately 50% present with metastatic, and
35% with locally advanced surgically unresectable disease. Locally advanced,
surgically unresectable proximal pancreatic tumours are defined as those that
encase adjacent arteries including the coeliac axis, superior mesenteric artery
(SMA) or both, or that occlude the portal vein (PV), superior mesenteric vein (SMV), or superior mesenteric portal vein (SMPV)
confluence (Tables 1 and 2). This paper reviews the literature on the
management of borderline resectable proximal pancreatic cancers with vascular
involvement with reference to assessment of resectability, staging
investigations, survival, pancreaticoduodenectomy (PD) with major arterial and
venous resection and the role of neoadjuvant therapy.Table 1
National comprehensive cancer network practice guidelines in oncology
for pancreatic adenocarcinoma-v.1.2008: criteria
defining resectability status [2].
ResectableHead/body/tail tumour(i) No distant metastases(ii) Clear fat plane around coeliac and SMA(iii) Patent SMV/PVBorderline resectableHead/body(i) Severe unilateral SMV/PV impingement(ii) Tumour abutment on SMA(iii) GDA encasement up to origin at HA(iv) Tumours with limited involvement of the IVC(v) SMV occlusion, if of a short segment, with open vein
both proximally and distally (unresectable if occlusion of the proximal
SMV up to the PV branches)(vi) Colon or mesocolon invasionTail(i) Adrenal, colon or mesocolon, kidney invasionUnresectableHead(i) Distant metastases(ii) SMA, coeliac artery encasement(iii) SMV/PV occlusion(iv) Aortic, IVC invasion or encasement(vi) Invasion of SMV below transverse colonBody(i) Distant metastases(ii) SMA, coeliac, HA encasement(iii) SMV/PV occlusion(iv) Aortic invasionTail(i) Distant metastases(ii) SMA, coeliac encasement(iii) Rib, vertebral invasionNodal status(i) Metastases to lymph nodes beyond the field of
resection.GDA = Gastroduodenal arteryIVC = Inferior vena cavaPV = Portal veinSMV = Superior mesenteric veinSMA = Superior mesenteric artery.Table 2
M. D. Anderson criteria for defining resectability status of pancreatic
cancer [3, 4].
Resectable(i) No distant metastases(ii) No extension to the SMA; normal fat plant between the
tumour and SMA(iii) No extension to the coeliac axis or HA(iv) Patent SMV/PVBorderline resectable(i) Tumour abutment≤180° (≤50%) of
the circumference of the SMA(ii) Short-segment encasement/abutment of the CHA
(typically at the GDA origin)(iii) Short-segment occlusion of the SMV/PV with suitable
vessel above and belowUnresectable(i) Encased SMA (>180°)(ii) Encased HA with no technical option for reconstruction(iii) Occluded SMV/PV wih no technical option for
reconstructionCHA = common hepatic arteryGDA = Gastroduodenal arteryHA = Hepatic arteryPV = Portal veinSMV = Superior mesenteric veinSMA = Superior mesenteric artery.


## 2. Discussion

### 2.1. Assessment of Resectability

Determining resectability
of the primary tumour is the most important goal in initial patient evaluation.
High-quality computed tomography (CT) scanning can be used to classify
pancreatic tumours into resectable (Stage I or II), locally advanced, surgically
unresectable (Stage III), or metastatic
disease (Stage IV). In recent years, with further advances in imaging
techniques with multidetector CT optimized for pancreatic imaging, a new subset
of tumours have emerged termed “borderline" or “marginally resectable" tumours
blurring the distinction between resectable and locally advanced, surgically
unresectable tumours [2, 3, 5]. There is currently no consensus in
the reported literature on the definition or management of borderline
resectable tumours. The National Comprehensive Cancer Network (NCCN) recently
defined borderline resectable tumours of the pancreatic head and body as those
with severe unilateral SMV/PV
impingement, tumour abutment on SMA, gastroduodenal artery (GDA) encasement up
to its origin from the hepatic artery (HA), tumours with limited inferior vena
cava (IVC) involvement, short-segment
SMV occlusion with proximal and
distal vein patency, and colon or mesocolon invasion (Table 1) [2]. Tumours are defined as unresectable
in the presence of proximal SMV occlusion up to the PV branches (Table 1) [2]. Neoadjuvant chemoradiotherapy is
advocated by the NCCN for any tumour where an incomplete R1 or R2 resection is
likely [2]. The M. D. Anderson criteria for
borderline resectable tumours include those with encasement of a short segment
of the HA amenable to resection and reconstruction without tumour extension to
the coeliac axis, abutment of the SMA involving ≤180° of the arterial
circumference, or short-segment occlusion of the SMV,
PV, or SMPV confluence with normal SMVbelow and normal PV above the area of tumour involvement amenable to resection
and reconstruction (Table 2) [3].


### 2.2. Staging Investigations

Multidetector CT imaging is regarded
as the optimal diagnostic and staging investigation [3, 6–11]. Freeny reported an accuracy
rate of 95–97% for detection
of pancreatic carcinomas, and 100% for predicting unresectability by helical CT [12]. In a
series of 46 patients with a suspected pancreatic tumour, Catalano et al.
demonstrated sensitivity, specificity, and accuracy of multidetector CT of 97%,
80%, and 96%, respectively, with correct prediction of unresectability with
sensitivity of 96%, specificity of 86%, and accuracy of 93% [13]. However, the ability of helical CT to
predict tumour resectability ranges from 57 to 88% [12, 12, 14, 14, 15]. Its major limitation is its low
sensitivity in the detection of small-volume disease with nondetection of small-volume
hepatic, serosal and/or peritoneal metastases. Despite advances in radiological
imaging techniques 20–35% of patients
thought to have resectable tumours have unsuspected metastases [15–18]. In many centres, laparoscopic
staging is an integral component in the preoperative staging protocols of
patients with radiological resectable disease to avoid unnecessary laparotomy.
Biopsy of suspicious liver serosal or peritoneal metastases inaccessible or too
small for interventional radiological techniques can be performed. Extra
pancreatic extension of tumour with colic or mesocolic involvement can be
determined. Improvements in technology and better patient selection have
reduced the benefit of staging laparoscopy. However, it continues to
consistently upstage patients with preoperative radiologically determined
resectable disease with a benefit in determining resectability of 15–20% [19, 20, 20–25]. Peritoneal cytology enhances the
sensitivity of staging laparoscopy upstaging an additional 8% of patients with
positive cytology and advanced unresectable pancreatic cancer [26–28]. In addition, laparoscopic
ultrasonography can be performed to improve the diagnostic accuracy of staging
laparoscopy with evaluation of regional nodal disease, local vascular
involvement, and to search for liver metastases [21, 25, 29–33].Critics of staging laparoscopy
believe inoperable disease secondary to local extension and vascular encasement
can only be determined by laparotomy [34]. In addition, many argue that
staging laparoscopy is of minimal benefit as patients with unresectable disease
will subsequently require a bypass procedure for biliary or gastric outlet
obstruction. Historically, reports of the development of obstructive jaundice
in as many as 70% and gastric outlet obstruction in up to 25% of patients with
unresectable pancreatic adenocarcinoma have supported the role of prophylactic
bypass [35–37]. More recent reports suggest a lower
incidence of biliary and gastric outlet obstruction [38]. Also, prophylactic palliative surgical bypass may be unnecessary. In a
study by Espat et al.,  only 3% of 155 patients
with laparoscopically staged unresectable histologically proven pancreatic
cancer required a subsequent surgical bypass [39].Other available investigative tools
include mesenteric angiography, which has been abandoned in most centres in
favour of multidetector CT, magnetic resonance techniques, transabdominal and
endoscopic ultrasonography (EUS), and intraoperative intraportal endovascular
ultrasonography (IPEUS) [3, 40, 41]. The combination of magnetic
resonance cholangiopancreatography and magnetic resonance angiography has a reported
accuracy of 89.7% in predicting resectability in patients with pancreatic head carcinoma [42, 43]. EUS has a role in the detection of
pancreatic cancer, tissue confirmation of malignancy by EUS-directed fine
needle aspiration (EUS-FNA), and determination of tumour resectability by
assessment of locoregional tumour extension [44–50]. EUS has been advocated as the
most sensitive method to assess small lesions <2 cm in diameter [47]. In a series by Brandwein et al., the finding of a focal
hypoechoic mass without other abnormalities predicted malignancy in patients
with ductal adenocarcinoma with an accuracy of 89%, specificity of only 22.2%,
and sensitivity of 100% as all patients with a pancreatic mass were evaluated [46]. Findings at EUS predicted tumour
resectability with an accuracy of 85%, specificity of 75%, and sensitivity of
100%, and EUS-FNA correctly detected malignancy with an accuracy of 65%,
specificity of 100%, and sensitivity of 59.5% [46]. Sensitivity and specificity rates
of EUS for confirming venous invasion range from 69% to 93% and 71% to 100%,
respectively [51–53]. Sensitivities of 59.5% to 91% have
been reported with EUS-FNA in the diagnosis of pancreatic malignancy [46, 54, 55]. To avoid the risk of tumour seeding
along needle tracts EUS-FNA is preferable to percutaneous approaches. The
presence of a cytologist at the time of the EUS with immediate evaluation of
the EUS-FNA specimen increases the accuracy of the procedure. However, cytological
interpretation of the tissue sample can be difficult due to the presence of
reactive atypia or a benign appearance of pancreatic ductal cells in a well differentiated pancreatic adenocarcinoma.Intraoperative intraportal
endovascular ultrasonography (IPEUS) is employed in a limited number of centres
to assess locoregional tumour extension, in particular PV invasion and invasion
of the second portion of the pancreatic head nerve plexus [56, 57]. Invasion of the extrapancreatic
nerve plexus is common in pancreatic head adenocarcinoma. In these cases,
achievement of an R0 resection would necessitate complete dissection of the
extrapancreatic nerve plexus and the nerve plexus around the SMA resulting in severe
diarrhoea. Nakao et al. advocate the use of IPEUS to evaluate for
extrapancreatic nerve plexus invasion. In the absence of invasion of the second
portion of the pancreatic head nerve plexus preservation of the left
semicircular nerve plexus around the SMA is recommended to prevent the
occurrence of postoperative diarrhoea
[57]. In the presence of extrapancreatic
nerve plexus invasion particularly to the nerve plexus around the SMA radical
resection is contraindicated [57].


### 2.3. Survival

The goal of surgery is to achieve an R0
resection. Margin resection status is an important prognostic factor, and a
margin-positive resection predicts early recurrence and reduced survival [3, 40, 58]. Previous reports suggest that
patients with a positive surgical margin following PD have a similar survival
rate to patients with locally advanced, surgically unresectable disease treated
nonoperatively with 5-fluorouracil-based chemotherapy and irradiation [10, 57]. However, in some series,
statistically significantly longer overall survival rates have been reported
after palliative PD for pancreatic head, neck, and uncinate process
adenocarcinoma than palliative surgical bypass or nonoperative candidates when performed in high-volume
centres with minimal morbidity and mortality, and combined with adjuvant
chemoradiotherapy [59, 60].Historically,
major vessel involvement has been a contraindication to resection in patients
with pancreatic adenocarcinoma. In 1973, Fortner described a surgical approach
of regional pancreatectomy involving en bloc resection of peripancreatic soft
tissue, regional lymph nodes with resection of the PV (Type I), or resection
and reconstruction of a major artery (Type II) [61]. Although these extended resections
achieved improved resectability rates, associated high morbidity (67%) and
mortality (23%) with low survival rates (3-year-survival rate 3%) discouraged
generalized adoption of major vessel resection and reconstruction. However,
since the 1970s there have been major advances in radiological and surgical
techniques resulting in improved preoperative staging, better patient
selection, and reduced surgical morbidity and mortality [3, 62]. Perioperative mortality rates of
less than 4% following PD are now achieved in high-volume centres [1, 40, 58]. In a consecutive series of 650 PD
procedures performed between 1990 and 1996 at The Johns Hopkins Medical
Institute, the mortality rate was 1.4%, with a reoperation rate for complications
of 4%, and a mean hospital length of stay of 13 days [63]. No death was observed in the last
190 consecutive patients who underwent PD [63].


### 2.4. Pancreaticoduodenectomy with Major Arterial Resection

Tumour encasement or abutment>180° of the arterial circumference of the SMA, or encasement of the coeliac
or HA remain contraindications to resection (Tables 1 and 2) [2, 3]. Tumour encasement of the SMA or coeliac
artery usually predicts extensive involvement of the mesenteric neural plexus
with an inability to achieve a negative retroperitoneal resection margin even
with radical extended surgery [3, 57]. PD with a histologically proven
positive retroperitoneal margin performed as part of a standard or extended
resection is associated with a median survival of less than one year [10]. Major arterial resection and
reconstruction has been associated with a high operative mortality and
morbidity in some series with poor long-term outcome [ 40]. A tumour is deemed unresectable if
the HA is encased with no technical option for reconstruction due to extension
to the coeliac axis/splenic/left gastric junction or coeliac origin (Tables 1 and
2) [2, 3]. Borderline unresectable tumours
with arterial involvement include those with tumour abutment of  ≤180° of the circumference of the SMA, tumour encasement of the GDA up to its originat the HA, or short-segment encasement/abutment of the common hepatic artery(CHA) or proper hepatic artery (PHA)typically at the GDA origin. Segmental resection of the HA with reconstructionis usually possible by primary end-to-end anastomosis because of the redundancy
of the artery, or by an interposition graft. This limited involvement of the
CHA/PHA is typically due to tumour extension in a cephalad
direction along the GDA. More subtle findings on multidetector CT can be
helpful in determining tumour resectability. The ability to achieve an R0 or R1
surgical resection is more likely in the presence of periarterial stranding
rather than dense tissue involving the artery [3].


### 2.5. Pancreaticoduodenectomy with Major Venous Resection

There are two important questions to ask when
considering PD with PV resection. Can PV resection be performed safely and does
SMV/PV involvement affect long-term survival? These questions
have been addressed in the published literature. In contrast to arterial
resection, PD with PV resection can be performed safely with no increase in
perioperative morbidity or mortality compared to standard PD [40, 57, 58, 64, 65]. Although in some studies PV
resection has been associated with longer operative time, higher blood loss,
greater transfusion requirements, and a longer length of hospital stay,
reported operative morbidity and mortality is comparable to standard PD [40, 58, 64–68]. A recent series by Yekebas et al.
demonstrated no statistical difference in operative time, intraoperative blood
transfusion requirements, vascular complications, in hospital morbidity or
mortality rates in 128 patients who underwent en bloc vascular resection
compared to 449 undergoing standard resection [11]. This series of 585 consecutive
patients included those with pancreatic, ampullary, and distal common bile duct
cancers who underwent potentially curative resection over an 11-year-period [11]. Final histopathology confirmed pancreatic
ductal adenocarcinoma in 482 of 585 patients (82%) of which 100 (21%) underwent
vascular resection [11]. In a series by Bachellier
et al., one of 31 patients died of mesenteric venous infarction 4 days following
PD with SMV-PV resection
resulting in a mortality rate of 3.2% [69, 70]. Of 21 patients who underwent PD with SMV-PV resection in the same series
from 1994 no postoperative deaths were observed [69, 70]. In Van
Geenen's et al., series of 250 consecutive PDs 34 (16%) underwent SMV-PV
resection, of which 28 had a tangential wedge and 6 a segmental resection [69, 70]. The overall mortality for the
series was 1.2%, with a 0% mortality after SMV-PV resection in the 34 patients [69, 70]. Although the numbers are small, these
reports demonstrate the feasibility and safety of PD with SMV-PV resection when
performed in centres with acceptable overall morbidity and mortality rates
following standard PD. In a recently published series by Nakao et al., major
vessel resection was performed in 201 of 289 (69%) patients who underwent
curative resection for invasive ductal carcinoma of the pancreas from 1981 to
2005 [40]. This group performs combined
resection of major vessels including the PV and visceral arteries if involved
with catheter bypass of the PV, extrapancreatic nerve plexus excision, and
extended lymphadenectomy including the paraaortic lymph nodes with
retroperitoneal connective tissue clearance. PV or SMV resection was performed in 200
patients, combined PV and arterial resection in 14, and hepatic arterial
resection without PV resection in one patient [40]. Operative mortality was 3.8% for
the 289 patients who underwent resection, 1.1% for patients without vascular
resection, 2.7% for patients with SMV/PV resection, and 35.7% for combined PV
and arterial resection [40]. The combined PV and arterial
resection group had a higher operative death rate, more advanced tumours, and a
higher incidence of positive dissected peripancreatic tissue margins [40].Involvement of the SMV,
PV, or SMPV confluence are not associated with histological variables
predicting a poor prognosis [64]. Involvement of the SMPV confluence
is thought to be a function of tumour location and size rather than an
indicator of aggressive tumour biology [1, 64]. 5-year-survival rates of 7.4% to 17%
have been reported in patients following PD with PV resection [1, 11, 57, 65]. However, 5-year-survival rates
after PD with PV resection are significantly better after an R0 resection than
an R1 or R2 resection [1, 40]. A higher incidence of perineural
invasion and a greater median tumour size has been reported in a small number
of studies in patients requiring PV resection [64, 65]. However, these variables have no
statistically significant influence on survival when analysed in univariate or
multivariate analysis [11, 65]. Importantly, patients who require PV
resection in the absence of tumour extension to the SMA or coeliac axis have
similar survival to patients undergoing standard PD [10, 71]. Nakao et al. have reported improved
cumulative 5-year-survival rates in patients with tumour-free margins after PD
with PV resection even in the presence of tumour invasion of the SMV-PV with a
negative arterial margin [40]. Complete PV encasement with
occlusion and thrombosis remains a contraindication to resection as arterial
involvement is likely. It is important to note that PV resection in published
series has been performed for clinical and/or radiological suspicion of PV
involvement. Pancreatic adenocarcinoma is known to induce an extensive
desmoplastic stromal reaction in surrounding tissues. Therefore, it can be
difficult to distinguish true PV invasion from tumour adherence to the PV by an
inflammatory reaction both on preoperative imaging and intraoperatively.
Importantly, the absence of histological PV invasion is reported in 18% to 50%
of cases with intraoperatively suspected vascular infiltration [11, 58, 65, 66, 69, 71–77]. Recently published series report
peritumoural inflammatory adherence to the vein wall in 23% of patients
suspected of vascular invasion [11, 71].While PV resection itself
is not a negative prognostic indicator, histologically proven PV invasion is
independently correlated with lower patient survival [11, 57, 68]. Patients who undergo PV resection
without true invasion of the vein wall have better survival than those with
histologically proven PV invasion [11, 57, 68]. In the presence of negative
dissected peripancreatic tissue margins, 2-year-survival is reduced in patients
with histologically proven positive PV wall invasion following extended PD [57]. The degree of PV wall invasion correlates
with outcome with reduced survival as the depth of invasion increases [68]. In a
report by Nakagohri et al., 60% of patients with invasion of the tunica
intima of the PV had extrapancreatic nerve plexus involvement [78]. In a recent study, Riediger et al.
reported 5-year-survival rates following PD with PV resection for pancreatic
head cancer of only 11% in the presence of histologically proven malignant PV invasion
compared to 51% for those without venous invasion [58]. However, this result should be
interpreted with caution as it represents a subgroup analysis in a total of 14
and 12 patients, respectively [58]. Other groups report equivalent
median survival of patients with histopathologically confirmed vascular
invasion compared to those without vascular invasion [11, 66, 76, 77].


### 2.6. The Role of Neoadjuvant Therapy

To maximize the potential for an R0 resection, Varadhachary et al. advocate neoadjuvant treatment with systemic chemotherapy followed by chemoradiation in patients with borderline resectable tumours
defined by the extent of local tumour growth on multidetector CT [3].
Following a 6 to 8 month course of neoadjuvant treatment, patients with
responding or stable disease undergo PD with vascular resection if required. Varadhachary
et al. describe their institutional experience with the use of differing protocols
of neoadjuvant systemic therapy followed by chemoradiation, and four
representative cases are presented [3].
Recent reports suggesting improved response rates, with acceptable tolerability
and short-term outcome with gemcitabine-based chemoradiation neoadjuvant
treatment protocols are promising [3, 79–83]. The optimal regimen of preoperative treatment has not been
defined to date, and is the subject of ongoing clinical research trials. Detailed
analysis of data from the Eastern Cooperative Oncology Group (ECOG 1200) phase
II prospective multicentre study is awaited [84]. This study was designed to determine the efficacy of 2 neodajuvant
chemoradiotherapeutic regimes, and the effect on margin-resection status in
patients with locally advanced, potentially resectable pancreatic
adenocarcinoma. Patients were randomized to receive neoadjuvant gemcitabine and
radiotherapy or gemcitabine, fluorouracil, and cisplatin followed by
radiotherapy and fluorouracil, followed by surgery and adjuvant chemotherapy [84].
Locoregional adjuvant chemotherapy may be of benefit in patients with positive
PV margins following extended PD with PV resection. In a pilot study of
postoperative intra-arterial chemotherapy improved survival to 25.6 months in
patients following PV resection with histologically proven PV invasion was
demonstrated versus 9.4 months without chemotherapy through reduction in the
occurrence of liver metastasis [85].
Although the results of this study need to be interpreted with caution due to
its small size further trials in this area are warranted.


## 2.1. Assessment of Resectability

Determining resectability
of the primary tumour is the most important goal in initial patient evaluation.
High-quality computed tomography (CT) scanning can be used to classify
pancreatic tumours into resectable (Stage I or II), locally advanced, surgically
unresectable (Stage III), or metastatic
disease (Stage IV). In recent years, with further advances in imaging
techniques with multidetector CT optimized for pancreatic imaging, a new subset
of tumours have emerged termed “borderline" or “marginally resectable" tumours
blurring the distinction between resectable and locally advanced, surgically
unresectable tumours [2, 3, 5]. There is currently no consensus in
the reported literature on the definition or management of borderline
resectable tumours. The National Comprehensive Cancer Network (NCCN) recently
defined borderline resectable tumours of the pancreatic head and body as those
with severe unilateral SMV/PV
impingement, tumour abutment on SMA, gastroduodenal artery (GDA) encasement up
to its origin from the hepatic artery (HA), tumours with limited inferior vena
cava (IVC) involvement, short-segment
SMV occlusion with proximal and
distal vein patency, and colon or mesocolon invasion (Table 1) [2]. Tumours are defined as unresectable
in the presence of proximal SMV occlusion up to the PV branches (Table 1) [2]. Neoadjuvant chemoradiotherapy is
advocated by the NCCN for any tumour where an incomplete R1 or R2 resection is
likely [2]. The M. D. Anderson criteria for
borderline resectable tumours include those with encasement of a short segment
of the HA amenable to resection and reconstruction without tumour extension to
the coeliac axis, abutment of the SMA involving ≤180° of the arterial
circumference, or short-segment occlusion of the SMV,
PV, or SMPV confluence with normal SMVbelow and normal PV above the area of tumour involvement amenable to resection
and reconstruction (Table 2) [3].


## 2.2. Staging Investigations

Multidetector CT imaging is regarded
as the optimal diagnostic and staging investigation [3, 6–11]. Freeny reported an accuracy
rate of 95–97% for detection
of pancreatic carcinomas, and 100% for predicting unresectability by helical CT [12]. In a
series of 46 patients with a suspected pancreatic tumour, Catalano et al.
demonstrated sensitivity, specificity, and accuracy of multidetector CT of 97%,
80%, and 96%, respectively, with correct prediction of unresectability with
sensitivity of 96%, specificity of 86%, and accuracy of 93% [13]. However, the ability of helical CT to
predict tumour resectability ranges from 57 to 88% [12, 12, 14, 14, 15]. Its major limitation is its low
sensitivity in the detection of small-volume disease with nondetection of small-volume
hepatic, serosal and/or peritoneal metastases. Despite advances in radiological
imaging techniques 20–35% of patients
thought to have resectable tumours have unsuspected metastases [15–18]. In many centres, laparoscopic
staging is an integral component in the preoperative staging protocols of
patients with radiological resectable disease to avoid unnecessary laparotomy.
Biopsy of suspicious liver serosal or peritoneal metastases inaccessible or too
small for interventional radiological techniques can be performed. Extra
pancreatic extension of tumour with colic or mesocolic involvement can be
determined. Improvements in technology and better patient selection have
reduced the benefit of staging laparoscopy. However, it continues to
consistently upstage patients with preoperative radiologically determined
resectable disease with a benefit in determining resectability of 15–20% [19, 20, 20–25]. Peritoneal cytology enhances the
sensitivity of staging laparoscopy upstaging an additional 8% of patients with
positive cytology and advanced unresectable pancreatic cancer [26–28]. In addition, laparoscopic
ultrasonography can be performed to improve the diagnostic accuracy of staging
laparoscopy with evaluation of regional nodal disease, local vascular
involvement, and to search for liver metastases [21, 25, 29–33].Critics of staging laparoscopy
believe inoperable disease secondary to local extension and vascular encasement
can only be determined by laparotomy [34]. In addition, many argue that
staging laparoscopy is of minimal benefit as patients with unresectable disease
will subsequently require a bypass procedure for biliary or gastric outlet
obstruction. Historically, reports of the development of obstructive jaundice
in as many as 70% and gastric outlet obstruction in up to 25% of patients with
unresectable pancreatic adenocarcinoma have supported the role of prophylactic
bypass [35–37]. More recent reports suggest a lower
incidence of biliary and gastric outlet obstruction [38]. Also, prophylactic palliative surgical bypass may be unnecessary. In a
study by Espat et al.,  only 3% of 155 patients
with laparoscopically staged unresectable histologically proven pancreatic
cancer required a subsequent surgical bypass [39].Other available investigative tools
include mesenteric angiography, which has been abandoned in most centres in
favour of multidetector CT, magnetic resonance techniques, transabdominal and
endoscopic ultrasonography (EUS), and intraoperative intraportal endovascular
ultrasonography (IPEUS) [3, 40, 41]. The combination of magnetic
resonance cholangiopancreatography and magnetic resonance angiography has a reported
accuracy of 89.7% in predicting resectability in patients with pancreatic head carcinoma [42, 43]. EUS has a role in the detection of
pancreatic cancer, tissue confirmation of malignancy by EUS-directed fine
needle aspiration (EUS-FNA), and determination of tumour resectability by
assessment of locoregional tumour extension [44–50]. EUS has been advocated as the
most sensitive method to assess small lesions <2 cm in diameter [47]. In a series by Brandwein et al., the finding of a focal
hypoechoic mass without other abnormalities predicted malignancy in patients
with ductal adenocarcinoma with an accuracy of 89%, specificity of only 22.2%,
and sensitivity of 100% as all patients with a pancreatic mass were evaluated [46]. Findings at EUS predicted tumour
resectability with an accuracy of 85%, specificity of 75%, and sensitivity of
100%, and EUS-FNA correctly detected malignancy with an accuracy of 65%,
specificity of 100%, and sensitivity of 59.5% [46]. Sensitivity and specificity rates
of EUS for confirming venous invasion range from 69% to 93% and 71% to 100%,
respectively [51–53]. Sensitivities of 59.5% to 91% have
been reported with EUS-FNA in the diagnosis of pancreatic malignancy [46, 54, 55]. To avoid the risk of tumour seeding
along needle tracts EUS-FNA is preferable to percutaneous approaches. The
presence of a cytologist at the time of the EUS with immediate evaluation of
the EUS-FNA specimen increases the accuracy of the procedure. However, cytological
interpretation of the tissue sample can be difficult due to the presence of
reactive atypia or a benign appearance of pancreatic ductal cells in a well differentiated pancreatic adenocarcinoma.Intraoperative intraportal
endovascular ultrasonography (IPEUS) is employed in a limited number of centres
to assess locoregional tumour extension, in particular PV invasion and invasion
of the second portion of the pancreatic head nerve plexus [56, 57]. Invasion of the extrapancreatic
nerve plexus is common in pancreatic head adenocarcinoma. In these cases,
achievement of an R0 resection would necessitate complete dissection of the
extrapancreatic nerve plexus and the nerve plexus around the SMA resulting in severe
diarrhoea. Nakao et al. advocate the use of IPEUS to evaluate for
extrapancreatic nerve plexus invasion. In the absence of invasion of the second
portion of the pancreatic head nerve plexus preservation of the left
semicircular nerve plexus around the SMA is recommended to prevent the
occurrence of postoperative diarrhoea
[57]. In the presence of extrapancreatic
nerve plexus invasion particularly to the nerve plexus around the SMA radical
resection is contraindicated [57].


## 2.3. Survival

The goal of surgery is to achieve an R0
resection. Margin resection status is an important prognostic factor, and a
margin-positive resection predicts early recurrence and reduced survival [3, 40, 58]. Previous reports suggest that
patients with a positive surgical margin following PD have a similar survival
rate to patients with locally advanced, surgically unresectable disease treated
nonoperatively with 5-fluorouracil-based chemotherapy and irradiation [10, 57]. However, in some series,
statistically significantly longer overall survival rates have been reported
after palliative PD for pancreatic head, neck, and uncinate process
adenocarcinoma than palliative surgical bypass or nonoperative candidates when performed in high-volume
centres with minimal morbidity and mortality, and combined with adjuvant
chemoradiotherapy [59, 60].Historically,
major vessel involvement has been a contraindication to resection in patients
with pancreatic adenocarcinoma. In 1973, Fortner described a surgical approach
of regional pancreatectomy involving en bloc resection of peripancreatic soft
tissue, regional lymph nodes with resection of the PV (Type I), or resection
and reconstruction of a major artery (Type II) [61]. Although these extended resections
achieved improved resectability rates, associated high morbidity (67%) and
mortality (23%) with low survival rates (3-year-survival rate 3%) discouraged
generalized adoption of major vessel resection and reconstruction. However,
since the 1970s there have been major advances in radiological and surgical
techniques resulting in improved preoperative staging, better patient
selection, and reduced surgical morbidity and mortality [3, 62]. Perioperative mortality rates of
less than 4% following PD are now achieved in high-volume centres [1, 40, 58]. In a consecutive series of 650 PD
procedures performed between 1990 and 1996 at The Johns Hopkins Medical
Institute, the mortality rate was 1.4%, with a reoperation rate for complications
of 4%, and a mean hospital length of stay of 13 days [63]. No death was observed in the last
190 consecutive patients who underwent PD [63].


## 2.4. Pancreaticoduodenectomy with Major Arterial Resection

Tumour encasement or abutment>180° of the arterial circumference of the SMA, or encasement of the coeliac
or HA remain contraindications to resection (Tables 1 and 2) [2, 3]. Tumour encasement of the SMA or coeliac
artery usually predicts extensive involvement of the mesenteric neural plexus
with an inability to achieve a negative retroperitoneal resection margin even
with radical extended surgery [3, 57]. PD with a histologically proven
positive retroperitoneal margin performed as part of a standard or extended
resection is associated with a median survival of less than one year [10]. Major arterial resection and
reconstruction has been associated with a high operative mortality and
morbidity in some series with poor long-term outcome [ 40]. A tumour is deemed unresectable if
the HA is encased with no technical option for reconstruction due to extension
to the coeliac axis/splenic/left gastric junction or coeliac origin (Tables 1 and
2) [2, 3]. Borderline unresectable tumours
with arterial involvement include those with tumour abutment of  ≤180° of the circumference of the SMA, tumour encasement of the GDA up to its originat the HA, or short-segment encasement/abutment of the common hepatic artery(CHA) or proper hepatic artery (PHA)typically at the GDA origin. Segmental resection of the HA with reconstructionis usually possible by primary end-to-end anastomosis because of the redundancy
of the artery, or by an interposition graft. This limited involvement of the
CHA/PHA is typically due to tumour extension in a cephalad
direction along the GDA. More subtle findings on multidetector CT can be
helpful in determining tumour resectability. The ability to achieve an R0 or R1
surgical resection is more likely in the presence of periarterial stranding
rather than dense tissue involving the artery [3].


## 2.5. Pancreaticoduodenectomy with Major Venous Resection

There are two important questions to ask when
considering PD with PV resection. Can PV resection be performed safely and does
SMV/PV involvement affect long-term survival? These questions
have been addressed in the published literature. In contrast to arterial
resection, PD with PV resection can be performed safely with no increase in
perioperative morbidity or mortality compared to standard PD [40, 57, 58, 64, 65]. Although in some studies PV
resection has been associated with longer operative time, higher blood loss,
greater transfusion requirements, and a longer length of hospital stay,
reported operative morbidity and mortality is comparable to standard PD [40, 58, 64–68]. A recent series by Yekebas et al.
demonstrated no statistical difference in operative time, intraoperative blood
transfusion requirements, vascular complications, in hospital morbidity or
mortality rates in 128 patients who underwent en bloc vascular resection
compared to 449 undergoing standard resection [11]. This series of 585 consecutive
patients included those with pancreatic, ampullary, and distal common bile duct
cancers who underwent potentially curative resection over an 11-year-period [11]. Final histopathology confirmed pancreatic
ductal adenocarcinoma in 482 of 585 patients (82%) of which 100 (21%) underwent
vascular resection [11]. In a series by Bachellier
et al., one of 31 patients died of mesenteric venous infarction 4 days following
PD with SMV-PV resection
resulting in a mortality rate of 3.2% [69, 70]. Of 21 patients who underwent PD with SMV-PV resection in the same series
from 1994 no postoperative deaths were observed [69, 70]. In Van
Geenen's et al., series of 250 consecutive PDs 34 (16%) underwent SMV-PV
resection, of which 28 had a tangential wedge and 6 a segmental resection [69, 70]. The overall mortality for the
series was 1.2%, with a 0% mortality after SMV-PV resection in the 34 patients [69, 70]. Although the numbers are small, these
reports demonstrate the feasibility and safety of PD with SMV-PV resection when
performed in centres with acceptable overall morbidity and mortality rates
following standard PD. In a recently published series by Nakao et al., major
vessel resection was performed in 201 of 289 (69%) patients who underwent
curative resection for invasive ductal carcinoma of the pancreas from 1981 to
2005 [40]. This group performs combined
resection of major vessels including the PV and visceral arteries if involved
with catheter bypass of the PV, extrapancreatic nerve plexus excision, and
extended lymphadenectomy including the paraaortic lymph nodes with
retroperitoneal connective tissue clearance. PV or SMV resection was performed in 200
patients, combined PV and arterial resection in 14, and hepatic arterial
resection without PV resection in one patient [40]. Operative mortality was 3.8% for
the 289 patients who underwent resection, 1.1% for patients without vascular
resection, 2.7% for patients with SMV/PV resection, and 35.7% for combined PV
and arterial resection [40]. The combined PV and arterial
resection group had a higher operative death rate, more advanced tumours, and a
higher incidence of positive dissected peripancreatic tissue margins [40].Involvement of the SMV,
PV, or SMPV confluence are not associated with histological variables
predicting a poor prognosis [64]. Involvement of the SMPV confluence
is thought to be a function of tumour location and size rather than an
indicator of aggressive tumour biology [1, 64]. 5-year-survival rates of 7.4% to 17%
have been reported in patients following PD with PV resection [1, 11, 57, 65]. However, 5-year-survival rates
after PD with PV resection are significantly better after an R0 resection than
an R1 or R2 resection [1, 40]. A higher incidence of perineural
invasion and a greater median tumour size has been reported in a small number
of studies in patients requiring PV resection [64, 65]. However, these variables have no
statistically significant influence on survival when analysed in univariate or
multivariate analysis [11, 65]. Importantly, patients who require PV
resection in the absence of tumour extension to the SMA or coeliac axis have
similar survival to patients undergoing standard PD [10, 71]. Nakao et al. have reported improved
cumulative 5-year-survival rates in patients with tumour-free margins after PD
with PV resection even in the presence of tumour invasion of the SMV-PV with a
negative arterial margin [40]. Complete PV encasement with
occlusion and thrombosis remains a contraindication to resection as arterial
involvement is likely. It is important to note that PV resection in published
series has been performed for clinical and/or radiological suspicion of PV
involvement. Pancreatic adenocarcinoma is known to induce an extensive
desmoplastic stromal reaction in surrounding tissues. Therefore, it can be
difficult to distinguish true PV invasion from tumour adherence to the PV by an
inflammatory reaction both on preoperative imaging and intraoperatively.
Importantly, the absence of histological PV invasion is reported in 18% to 50%
of cases with intraoperatively suspected vascular infiltration [11, 58, 65, 66, 69, 71–77]. Recently published series report
peritumoural inflammatory adherence to the vein wall in 23% of patients
suspected of vascular invasion [11, 71].While PV resection itself
is not a negative prognostic indicator, histologically proven PV invasion is
independently correlated with lower patient survival [11, 57, 68]. Patients who undergo PV resection
without true invasion of the vein wall have better survival than those with
histologically proven PV invasion [11, 57, 68]. In the presence of negative
dissected peripancreatic tissue margins, 2-year-survival is reduced in patients
with histologically proven positive PV wall invasion following extended PD [57]. The degree of PV wall invasion correlates
with outcome with reduced survival as the depth of invasion increases [68]. In a
report by Nakagohri et al., 60% of patients with invasion of the tunica
intima of the PV had extrapancreatic nerve plexus involvement [78]. In a recent study, Riediger et al.
reported 5-year-survival rates following PD with PV resection for pancreatic
head cancer of only 11% in the presence of histologically proven malignant PV invasion
compared to 51% for those without venous invasion [58]. However, this result should be
interpreted with caution as it represents a subgroup analysis in a total of 14
and 12 patients, respectively [58]. Other groups report equivalent
median survival of patients with histopathologically confirmed vascular
invasion compared to those without vascular invasion [11, 66, 76, 77].


## 2.6. The Role of Neoadjuvant Therapy

To maximize the potential for an R0 resection, Varadhachary et al. advocate neoadjuvant treatment with systemic chemotherapy followed by chemoradiation in patients with borderline resectable tumours
defined by the extent of local tumour growth on multidetector CT [3].
Following a 6 to 8 month course of neoadjuvant treatment, patients with
responding or stable disease undergo PD with vascular resection if required. Varadhachary
et al. describe their institutional experience with the use of differing protocols
of neoadjuvant systemic therapy followed by chemoradiation, and four
representative cases are presented [3].
Recent reports suggesting improved response rates, with acceptable tolerability
and short-term outcome with gemcitabine-based chemoradiation neoadjuvant
treatment protocols are promising [3, 79–83]. The optimal regimen of preoperative treatment has not been
defined to date, and is the subject of ongoing clinical research trials. Detailed
analysis of data from the Eastern Cooperative Oncology Group (ECOG 1200) phase
II prospective multicentre study is awaited [84]. This study was designed to determine the efficacy of 2 neodajuvant
chemoradiotherapeutic regimes, and the effect on margin-resection status in
patients with locally advanced, potentially resectable pancreatic
adenocarcinoma. Patients were randomized to receive neoadjuvant gemcitabine and
radiotherapy or gemcitabine, fluorouracil, and cisplatin followed by
radiotherapy and fluorouracil, followed by surgery and adjuvant chemotherapy [84].
Locoregional adjuvant chemotherapy may be of benefit in patients with positive
PV margins following extended PD with PV resection. In a pilot study of
postoperative intra-arterial chemotherapy improved survival to 25.6 months in
patients following PV resection with histologically proven PV invasion was
demonstrated versus 9.4 months without chemotherapy through reduction in the
occurrence of liver metastasis [85].
Although the results of this study need to be interpreted with caution due to
its small size further trials in this area are warranted.


## 3. Conclusion

Major vessel involvement should not be considered a
contraindication to resection of borderline resectable pancreatic
adenocarcinoma when a margin-negative resection is anticipated, and the
procedure is performed in a high-volume centre with acceptable morbidity and
mortality rates. In our institution, all patients with suspected SMV/PV involvement
in the absence of distant metastatic disease, where segmental resection and reconstruction are feasible, are considered
candidates for PD with concomitant major vessel resection. Tumour encasement of
the SMA, coeliac or HA remains contraindications to resection due to the
inability to achieve a margin negative resection, and high operative mortality
and morbidity. Patients with limited involvement of the CHA/PHA due to
tumour extension in a cephalad direction along the GDA are considered
candidates for PD with concomitant major vessel resection where segmental resection and reconstruction are
feasible with minimal morbidity and mortality. Neoadjuvant treatment
with systemic chemotherapy followed by chemoradiation as part of a clinical
trial should be offered to all patients with borderline resectable tumours when
an incomplete (R1 or R2) resection is anticipated.



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*Source: 839503-2009-03-11.xml*