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Review
Dig Surg 1999;16:327–336
Prevention and Treatment of
Complications in Pancreatic Cancer
Surgery
Pascal O. Berberat Helmut Friess
Markus W. Büchler
Jörg Kleeff Waldemar Uhl
Department of Visceral and Transplantation Surgery, University of Bern, Inselspital, Bern, Switzerland
Key Words
Postoperative complications W Fistulas W Hemorrhage W
Delayed gastric emptying W Octreotide W Pancreatic
cancer surgery W Pancreatic resection
Summary
Pancreatic cancer is the fourth leading cause of death from
malignant disease in Western industrialized countries. It is
a devastating disease with a very poor prognosis and has
a death rate roughly equal to its incidence rate. As this
tumor is resistant to all medical treatment options, such as
radio- and chemotherapy, radical surgical resection is the
only chance of cure so far. Significant advances have been
made over the past decades in pancreaticoduodenectomy, which is the standard operation in patients with pancreatic head cancer or periampullary cancer. In specialized
centers the operative mortality has fallen under 5%. However, the postoperative complication rates after this demanding procedure are still between 30 and 40%. Complications are mainly due to the technical difficulty of performing a safe and proper anastomosis between the stomach or small bowel and the soft pancreas. This article
reviews the treatment of the complications most frequently occurring after pancreatic cancer surgery, such as leakage of pancreatic anastomosis, pancreatic fistula, abscess
and hemorrhage. Furthermore, we discuss the management of these complications and how complications following pancreatic surgery can be prevented.
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Introduction
Pancreatic cancer is the fourth leading cause of death
from malignant disease in Western industrialized countries. It is a devastating disease with a very poor prognosis
and has a death rate roughly equal to its incidence rate [1,
2]. Contributing to the high death rate is the often late diagnosis – at a stage when the tumor has already metastasized
and the possibility of a curative resection is greatly reduced
– and the unresponsiveness to conventional oncological
treatment options. Although chemotherapy has improved
prognosis in many malignancies, its impact on pancreatic
cancer is limited [3]. The same is true of intraoperative or
external radiotherapy, antihormonal treatment and immunotherapy [4–7]. Due to the lack of effective adjuvant treatment protocols, the median survival time following diagnosis in nonresectable tumors is only about 4–6 months.
For cancers without distant metastases, resectability
rates have increased steadily during the past several
decades, due in part to improved diagnostic techniques
and lower postoperative mortality and morbidity in experienced centers of pancreatic surgery [8–17]. However,
long-term survival after resection continues to be low.
Recent studies indicate that the 5-year survival rate following resection for pancreatic cancer is only around 10%
[10–12], with a range between 0.4 and 33% [8–12].
Despite this, the fact remains that pancreatic resection
represents the only chance for cure, and often also the best
chance for palliation.
M.W. Büchler, MD
Department of Visceral and Transplantation Surgery
University of Bern, Inselspital
CH–3010 Bern (Switzerland)
Tel. +41 31 632 2404, Fax +41 31 382 4772, E-Mail [email protected]
It has been possible in recent years to substantially
reduce mortality and morbidity following pancreatic resection by improving surgical skill and perioperative care.
Many specialized centers have reported mortality rates
after Whipple resection around or even under 5% [8, 11,
14–17]. However, the postoperative complication rate
after pancreatic resection is still between 30 and 40% [8,
11, 14–17]. Morbidity results from surgical and nonsurgical postoperative complications, which can be subdivided
into early and late events in the postoperative course.
The so-called ‘nonsurgical’ complications include
mainly cardiopulmonary disturbances, renal failure and
metabolic disorders, such as pancreatic exocrine and endocrine insufficiency. These postoperative complications
are common sequelae of major operations and will not be
discussed further in this article.
The most feared surgical complications are leakage of
the intestinopancreatic anastomosis and hemorrhage. But
the other leading causes of postoperative morbidity – such
as pancreatic fistulas, intra-abdominal abscess, and delayed gastric emptying – are major factors in reduced
quality of life and provide longer hospitalization time and
therefore increased health costs.
In this article, we review the major surgical postoperative complications, discuss their prevention and treatment, and finally evaluate whether the chosen surgical
technique influences the frequency and severity of complications following pancreatic resection.
Surgical Complications following Pancreatic
Resection
Pancreatic Fistulas and Leakage of the
Pancreaticointestinal Anastomosis
A pancreatic fistula, the second leading cause of morbidity in pancreatic cancer patients after delayed gastric
emptying, is often an undiscovered harmless event. It
occurs in 4–24% of patients after pancreaticojejunostomy
[18]. However, if it progresses to a real anastomotic leak
with consequent sepsis and hemorrhage, it is the major
cause of postoperative mortality. Large series with pancreatic resection have shown that if a pancreatic leakage
occurs after pancreaticoduodenectomy, 20–40% [14–16,
19] of the patients die in the further postoperative course.
Fortunately, in specialized surgical centers a serious anastomotic leakage is a rare event (!5%), but if it happens it
frequently ends in catastrophe, with either long hospitalization or death.
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Risk Factors for Pancreatic Fistulas and Leakage of the
Pancreaticointestinal Anastomosis. In the last decades
several risk factors for pancreatic fistulas and/or leakage
of the anastomosis – such as soft pancreatic texture, a
small pancreatic duct, high pancreatic juice output, increased intraoperative blood loss, presence of jaundice,
operative technique and older patient age – have been
described. It seems that four main factors are associated
with the risk of developing pancreatic fistulas and/or a
leakage of the pancreaticointestinal anastomosis postoperatively: (1) soft texture of the pancreatic remnant in
pancreatic cancer patients; (2) the side of the pancreatic
remnant; (3) continuous exocrine pancreatic secretion
that may cause tension on the pancreatico-intestinal anastomosis, and (4) the technical difficulties of performing a
proper and safe anastomosis between the stomach or
small bowel and the pancreas.
First the consistency of the pancreatic parenchyma
seems to be a critical aspect for the security of the pancreaticointestinal anastomosis [20–22]. A review of 2,664
patients who had undergone Whipple resection reported a
postoperative fistula rate of 5% in chronic pancreatitis,
12% in pancreatic cancer, 15% in ampullary cancer and
33% in bile duct cancer. In those patients who had fistulas, the mortality rate due to a pancreatic fistula was 9, 31,
27 and 70%, in chronic pancreatitis, pancreatic cancer,
ampullary cancer, and bile duct cancer, respectively [20].
This supports the hypothesis that complications are closely related to the morphology of the pancreatic remnant. A
recent analysis also compared postoperative complications to the size and degree of fibrosis of the remnant
gland. There was a clear relationship between complications and the secretion capacity of the remaining pancreas
[22]. Experienced pancreatic surgeons are well aware of
this phenomenon. It is widely accepted that a fibrotic pancreatic remnant, as commonly found in chronic pancreatitis, facilitates the anastomosis, whereas in pancreatic
cancer, the soft and friable parenchyma of the remnant
pancreas makes the pancreaticointestinal anastomosis
difficult to perform [20, 23]. Several studies have shown
that normal preoperative exocrine function test results are
associated with a lower degree of pancreatic fibrosis and
consequently a higher incidence of postoperative pancreatic fistulas and leakage [21, 24, 25].
Not only has it been shown that pancreatic cancer
patients have a softer, more difficult-to-handle pancreatic
parenchyma, but they produce higher output of pancreatic juice postoperatively [26]. It is therefore reasonable to
assume that the inhibition of exocrine pancreatic secretion should improve the postoperative course and conse-
Berberat/Friess/Kleeff/Uhl/Büchler
quently reduce postoperative complications. In several
placebo-controlled, randomized trials it was demonstrated that perioperative prophylactic use of octreotide, a
somatostatin analogue which is able to reduce pancreatic
secretion, can significantly reduce pancreatic fistulas and/
or leakage of the pancreaticointestinal anastomosis [23,
27–32]. We will discuss this topic in more detail in the
second part of this review.
To avoid complications following pancreatic resection,
the surgical technique used to manage the pancreatic remnant seems to be of major importance.
Safe Surgical Techniques – Best Prevention of Postoperative Complications. Several surgical techniques have
been proposed in the past to achieve optimal management
of the pancreatic remnant with low pancreatic fistula and/
or leakage rates. These include procedures such as endto-side pancreaticojejunostomy, end-to-end pancreaticojejunal invagination, pancreaticogastrostomy, and pancreatic ductal occlusion or drainage.
Performance of pancreatic duct closure by ligation, stapling or suturing without anastomosis leads to inevitable
pancreatic fistula rates of 50–100%, with subsequent
complete exocrine pancreatic insufficiency, including steatorrhea and diarrhea, making this method clearly unfavorable. Minor modifications, such as external stenting of
the duct [33], the use of separated Roux loops [34], and
sealing of the pancreaticojejunostomy with fibrin glue
[35, 36], seem to have only a minor effect on the integrity
of the anastomosis. In a recent prospective but not randomized study, a reduction in the pancreatic fistula rate
from 29 to 7% was achieved by performing temporary
stented external drainage [37]. Other groups have not seen
any advantages to using stents [38–40]. However, there
are currently no randomized data available to show
whether perioperative stenting of the main pancreatic
duct is of any benefit following Whipple resection.
In the past, several groups have reported the superiority of pancreaticogastrostomy in comparison with pancreaticojejunostomy for reconstruction of pancreatic juice
flow following Whipple resection [41–44]. However, a
recent prospective randomized trial by Yeo et al. [45] was
not able to support this assumption: they showed similar
pancreatic fistula rates after pancreaticogastrostomy
(12.3%) and pancreaticojejunostomy (11.1%), indicating
that the experience of the surgeon doing the pancreaticointestinal anastomosis is of more importance than the
type of reconstruction.
Major debate is still going on concerning the technique and the site of the anastomosis: invagination vs.
duct-to-mucosa and end-to-end vs. end-to-side, respec-
tively. In prospective/retrospective uncontrolled studies,
some groups have reported higher incidences of pancreatic fistulas with the end-to-side compared with the
end-to-end anastomosis in pancreatic cancer surgery (15–
17 vs. 3–11%, respectively) [46, 47]. Consequently, these
groups suggest performing end-to-side anastomoses only
in patients with a dilated pancreatic duct and firm pancreatic parenchyma, frequently found in chronic pancreatitis or in obstructive pancreatic cancer. In contrast, other centers were not able to observe any differences in
postoperative morbidity and fistula rate between the different surgical techniques [48–51]. At the University of
Bern we perform a pancreaticojejunostomy in an end-toside technique with a duct-to-mucosa anastomosis. This
technique can be performed with any size duct and any
texture of the pancreas. Using interrupted two-layer endto-side pancreaticojejunostomy with an additional 6
stitches suturing the duct to ensure direct anastomosis of
the pancreatic to the jejunal mucosa (duct-to-mucosa),
we experienced a pancreatic fistula rate of 3% in 103
patients. In our experience the major advantages of the
end-to-side anastomosis are that there are no sequelae
with adjustable lumens between the jejunum and the
pancreatic remnant, and therefore optimal conditions for
a tension-free anastomosis, as also shown in experimental studies [16, 52]. However, all these technical issues
will remain controversial until prospective randomized
studies become available. As it seems no universal agreement will be reached in the near future, the preference of
the surgeon and the technique with which the surgeon
feels comfortable will decide which type of anastomosis
is performed.
However, in general a gentle handling of the remaining
pancreatic stump in combination with careful and subtle
handling of the pancreas has a greater effect on the postoperative outcome than which type of pancreatic anastomosis is done.
Treatment of Pancreatic Fistulas and Leakage. If, in
spite of safe surgical technique, a pancreatic fistula or
even leakage occurs, it is of major importance that a drain
has been placed in the neighborhood of the pancreaticoenteric anastomosis. Early recognition is most important for the successful treatment and favorable outcome
of a leakage of the pancreaticointestinal anastomosis. The
drainage volume and the amylase content should be monitored carefully. In addition, we rely on the clinical status,
the abdominal status and the general appearance of the
patient. Most pancreatic fistulas and/or leakages of the
pancreaticointestinal anastomosis are recognized between the 3rd and the 7th postoperative days: drainage
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Dig Surg 1999;16:327–336
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output increases and takes on a brownish-black color as
the amylase content increases. Finally, patients frequently
show signs of sepsis, such as tachycardia, tachypnea, rise
of temperature, abdomen tenderness, oliguria and increasing restlessness.
Treatment has to be individualized according to the
patient’s clinical situation. If there are no signs of local
peritonitis or ongoing bleeding in a clinically stable patient, one can approach the problem conservatively with
total parenteral feeding and close observation. Furthermore, it is mandatory to leave the drain in position and to
perform an abdominal CT scan to exclude intra-abdominal fluid collection or even an abscess.
Administration of a somatostatin analog (octreotide)
to reduce the pancreatic secretion can be optionally added. A randomized open trial suggested that administration of somatostatin shortens the spontaneous closure
time of postoperative pancreatic fistulas [53]. Another
multicenter, prospective, randomized, placebo-controlled, double-blind trial found no influence on fistula
closure time and clinical outcome with administration of
early octreotide [54]. However more randomized, placebo-controlled studies to evaluate the effectiveness of this
treatment need to be done. The majority of patients (70–
90%) with a low-output pancreatic fistula can be successfully managed conservatively.
However, when there is any doubt about the stability of
the clinical situation or if there are signs of ongoing or
recurrent hemorrhage, it is of great importance to perform
early surgical reintervention. In most patients, a ‘completion pancreatectomy’ solves the problem effectively. In
patients in whom a ‘completion pancreatectomy’ is not
possible, operative lavage or placement of additional
drains can be tried. However, the latter is often an unsatisfactory solution and is often associated with dismal prognosis [16]. It is not advisable to construct a new anastomosis or to sew over the leaking holes of the pancreaticointestinal anastomosis. By following the principle of early ‘completion pancreatectomy’ before sepsis occurs, up to 50% of
the patients can be salvaged [19, 25, 55, 56].
Intraabdominal Abscess
Intraabdominal abscesses are mostly the consequence
of pancreatic fistulas and/or leakage of the pancreaticointestinal or biliary anastomosis [57], and are seen in 10% of
patients after pancreaticoduodenectomy [11, 57, 58].
They are often associated with increased morbidity due to
the development of sepsis. On the abdominal CT one
should not confuse intraabdominal fluid collection, which
is a common condition in the early postoperative course
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after a pancreaticoduodenectomy, with the serious finding of an abscess. The former is mostly not of significance
and will resolve spontaneously. Rarely, there are also
abscesses due to the insufficiency of the hepaticojejunostomy, the gastrojejunostomy or the jejunojejunostomy.
These abscesses are mainly localized in the right subhepatic region or under the left diaphragm.
The treatment of choice is drainage by a percutaneous
catheter, which is introduced under ultrasonographic or
CT guidance. In addition, adequate intravenous antibiotics should be administered.
Most of the patients can successfully be treated by
these measures if the underlying cause (fistula leakage) is
also controlled. If there is no improvement in the clinical
condition of the patient, surgical reintervention should be
launched, with extensive lavage and placement of drains.
If there is any sign of anastomosis leakage as the underlying problem, a ‘completion pancreatectomy’ or sufficient
drainage of the leakage is the therapy of choice [57].
Hemorrhage
Besides leakage of the pancreaticointestinal anastomosis, the second most feared complication after pancreaticoduodenectomy is postoperative hemorrhage. In the literature hemorrhage is reported in 5–16% of these patients
[58–62]. In case of pancreaticointestinal anastomosis
leakage, the occurrence of postoperative hemorrhage is
associated with a mortality rate of between 15 and 58%
[59, 60]. Postoperative hemorrhage can be subdivided
into 2 groups of different origin: intraabdominal bleeding
(mostly from the retroperitoneal operation field) and gastrointestinal bleeding (intraluminal). Furthermore, we
can distinguish early postoperative bleeding within the
first 24 h from late bleeding which occurs in the 2nd or
3rd week after the operation.
Bleeding which occurs within the first 24 h postoperatively is mostly caused by insufficient intraoperative hemostasis, as can happen after all major abdominal operations. By monitoring the output of the drains and controlling the hemoglobin levels and the vital signs of the
patient, postoperative bleeding can be recognized early. If
the first sign is bloody output of the nasogastric tube and/
or melena, careful gastroscopy is the first diagnostic procedure which is performed. Suture line bleeding can often
be recognized easily in this way. If endoscopic intervention fails and there is no stabilization by administrating
blood and fresh frozen plasma, reoperation is the therapy
of choice. ‘Stress’ ulcers are always feared but rarely seen
following pancreaticoduodenectomy [59].
Berberat/Friess/Kleeff/Uhl/Büchler
A major portion of early postoperative bleeding is
caused by diffuse hemorrhage from the retroperitoneal
operation field. In a large series, the Mannheim group
found no difference between jaundiced and nonjaundiced
patients in the incidence of diffuse operative field bleeding [59]. Therefore, coagulation disturbances, which are
frequently seen in jaundiced patients, seem not to be the
reason for early diffuse bleeding. Concerning the higher
incidence of gastrointestinal bleeding in jaundiced patients, contradictory findings are reported: Some groups
have shown that high serum bilirubin levels are correlated
with a higher frequency of bleeding complications after
pancreatic surgery [59, 60, 63, 64]. In contrast, other studies were not able to find such a correlation [65].
Close attention should be paid if hemorrhage occurs in
the later postoperative course. Anastomotic suture bleeding or marginal ulcers can be the reasons for late postoperative bleeding. However, gastrointestinal hemorrhage often masks erosive bleeding from retroperitoneal vessels
(‘sentinel bleed’), which is caused by a leakage of the pancreatic anastomosis [66]. If gastroscopy does not demonstrate a clear source of gastrointestinal (intraluminal)
bleeding, the integrity of the pancreatic anastomosis has
to be evaluated carefully. If there is any suspicion of leakage of the anastomosis, or if there is already a known fistula, reoperation is imperative.
The best way to prevent postoperative hemorrhage is
to perform a proper operation with a careful hemostasis.
Skillful management of the pancreatic stump is of special
importance in order to prevent pancreatic anastomosis
leakage and the consequent danger of erosive bleeding. In
terms of prevention of hemorrhage, in jaundiced patients
preoperative bile drainage into the duodenum can be
achieved by endoscopic retrograde cholangiopancreatography (ERCP) or percutaneous transhepatic cholangio
drainage (PTCD). It is well documented that patients with
obstructive jaundice have a higher incidence of postoperative complications [67–69]. However, whether preoperative stenting of these patients influences the postoperative
complication rate, and above which bilirubin level bile
drainage should be recommended are still being debated
[18, 59, 65, 70–73]. Prospective, randomized trials are
awaited to bring a final solution to this controversy.
‘Stress’ ulcers can easily be prevented by the perioperative use of acid secretion inhibitory agents, such as proton pump inhibitors or H2-antagonists. Bleeding from
stress ulcers can mostly be resolved by interventional
endoscopy.
Delayed Gastric Emptying
Delayed gastric emptying is the leading cause of postoperative morbidity after pancreaticoduodenectomy. Although it is not associated with higher mortality, its
occurrence results in longer hospitalization [45, 50], reduced quality of life and increasing health costs. It occurs
in about one third of patients after pancreaticoduodenectomy (a range of 25–70% is described in the literature)
[45, 50, 74–76]. The wide range of incidence of delayed
gastric emptying in several studies is probably based on
different definitions of this complication. We define delayed gastric emptying as persistent secretion via the gastric tube of more than 500 ml/day over more than 5 days
after surgery, or recurrent vomiting in combination with
swelling of the gastrojejunostomy/duodenojejunostomy
and dilatation of the stomach in the contrast medium
passage.
The incidence of delayed gastric emptying does not
seem to increase with preservation of the pylorus, as initially thought [74, 76]. The most important risk factors for
delayed gastric emptying are the presence of intraabdominal complications [74] and the radicality of the resection
(lymph node dissection) [77, 78]. Cameron et al. [11]
demonstrated that after extended retroperitoneal lymphadenectomy, delayed gastric emptying is significantly increased (16 vs. 4%, p = 0.03). This observation supports
the general idea that delayed gastric emptying is caused by
gastric atony resulting from disruption of the gastroduodenal neural network. Another hypothesis postulates that
the circulating levels of motilin, a hormone which stimulates gastric motility and which is mainly produced in the
duodenum and the proximal jejunum, are significantly
reduced by the resection of the duodenum [79]. Based on
this hypothesis, a prospective, randomized, placebo-controlled study that administered the motilin agonist, erythromycin, found a tendency (not significant) toward reduced postoperative delayed gastric emptying (19 vs. 30%
in the verum group) [45].
Other treatment options are prokinetic agents, such
as metoclopramide and/or cisapride. However, none of
them has been tested in randomized controlled trials, and
therefore their efficacy in treating delayed gastric emptying is not proven. It should be noted that erythromycin is
not allowed to be administered in combination with cisapride in the treatment of delayed gastric emptying. Furthermore decompression of the stomach via the nasogastric tube and nutritional support via the parenteral or
enteral route should be performed. In most cases, delayed
gastric emptying resolves with these measures within 2–4
weeks. It is most important not to lose patience and to
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Surgery
Dig Surg 1999;16:327–336
331
inform the patient that it is only a matter of time until the
stomach adapts to the new situation.
Classical versus Pylorus-Preserving Whipple:
Influence on Postoperative Complications
Two resection procedures are mainly used today in
pancreatic cancer surgery – the classical Whipple resection and the pylorus-preserving Whipple resection. The
classical Whipple resection was introduced by Kausch in
1909 and reintroduced by Whipple in 1935 [80]. It was for
a long time the standard surgical therapy for malignant
processes in the pancreatic head region. With the intention of reducing postoperative morbidity without compromising adequate radicality, various modifications of
the original Whipple procedure have been proposed. The
most important was the introduction of the pylorus-preserving Whipple resection by Traverso and Longmire
[81], which was first performed by Watson [82] in 1945.
By preserving the stomach, the pylorus and the first part
of the duodenum, the pylorus-preserving Whipple resection protects against gastric dumping, marginal ulceration, and bile-reflux gastritis. Whether this operation is
sufficiently radical to treat pancreatic cancer is still debated [83–85]. However, several retrospective studies
were not able to show any difference in postoperative survival between the classical and the pylorus-preserving
Whipple in pancreatic cancer patients [84, 85]. With
regard to postoperative mortality and morbidity, the pylorus-preserving Whipple resection shows similar or even
better results [14, 86]. In addition, quality of life seems to
be better following the pylorus-preserving Whipple resection than after the classical Whipple resection [84].
Preliminary data from our own randomized prospective trial enrolling 114 consecutive patients show a significant reduction in cumulative morbidity after the pyloruspreserving Whipple resection compared with the classical
Whipple (57 vs. 72%, p = 0.05) [87]. There were no significant differences seen in postoperative surgical or medical
complications [87, 88]. Another recently published randomized controlled clinical trial showed a marginally significant higher incidence of delayed gastric emptying after
pylorus-preserving Whipple resection [89]. However, because only 31 patients were included, the statistical power
was not sufficient to draw final conclusions.
It seems that the classical Whipple resection and the
pylorus-preserving Whipple resection are providing similar results concerning long-term survival and postoperative mortality and morbidity [87, 88]. As the pylorus-pre-
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serving Whipple resection includes a significant reduction
of the operation time, the intraoperative blood loss and
the consequent need for blood substitution [84, 86, 89], it
should become the procedure of choice in treating pancreatic head cancer if oncological radicality is not compromised.
Standard versus Radical Resection in
Pancreatic Cancer: Influence on Postoperative
Complications
During the long era of pancreatic cancer surgery, major
progress in the technical performance of the operations,
but not in the long-term prognosis of the patient, has been
achieved. Therefore, it was always a goal to improve longterm survival as well by extending the resection. In 1973,
Fortner [13] performed a so-called ‘regional pancreatectomy’ by resecting the entire pancreas with en bloc removal
of the surrounding soft tissue and the regional lymph
nodes. The idea of extended radicality was mainly supported and further developed by several Japanese groups
in the last decade [90–92]. By providing an extended retroperitoneal lymphadenectomy they reported improvement of the 5-year survival up to 40% in retrospective and
nonrandomized studies [90–92]. In two recently published prospective randomized trials in Europe and the
United States, no significant survival benefit was reported
for extended resection procedures. There seems to be a
distinct trend toward longer survival [77, 78], but longer
follow-up is needed for a definitive conclusion.
In this context it has to be discussed whether more
radical and extended operations are causing higher perioperative mortality and morbidity. Does the additional
retroperitoneal lymphadenectomy cause more postoperative complications? There are reports of disabling watery
diarrhea as a new common postoperative complication
after extended resection for pancreatic cancer [91]. The
two randomized trials demonstrated no difference in
mortality and morbidity between standard and extended
resection [77, 78]. However, Yeo et al. [77] reported a significant difference in the occurrence of early delayed gastric emptying between the 2 groups (4 vs.16%, p = 0.03).
The presently available data provide evidence that a
pancreaticoduodenectomy with extended retroperitoneal
lymphadenectomy can be performed safely in specialized
centers, without additional risk of postoperative complications. Whether radical resection provides a survival
benefit for the patients in comparison to standard resection has to be investigated in future randomized studies.
Berberat/Friess/Kleeff/Uhl/Büchler
The Role of Octreotide in Prevention of
Complications
Postoperative complications are often caused by pancreatic juice that leaks from the pancreatic remnant and
reaches the peripancreatic region, or even the free abdominal cavity. The subsequent actions of activated proteases
can cause severe inflammation, and may lead to the
autodestruction of peripancreatic tissues and sudden lifethreatening hemorrhage. This sequence of events explains
the sometimes fatal outcome after leakage of the pancreatic anastomosis [93, 94]. It is therefore reasonable to
assume that inhibition of exocrine pancreatic secretion
should improve the postoperative course and consequently reduce postoperative complications.
Somatostatin, a tetradecapeptide originally discovered
in hypothalamic tissue, is a powerful inhibitor of basal
and stimulated exocrine pancreatic secretion [95, 96]. Its
action on the pancreas is mediated via the inhibition of
secretagogue gastrointestinal hormones and by direct
pathways via somatostatin receptors on acinar cells [97].
The concept of perioperative inhibition of exocrine pancreatic secretion by intravenous somatostatin infusion
dates back to 1979. In an open trial, Klempa et al. [98]
were able to show a drop in postoperative morbidity,
including the reduced occurrence of acute pancreatitis,
following Whipple’s resection.
Two other groups used octreotide, the octapeptide analogue of somatostatin, to prevent pancreatic fistula and
acute pancreatitis following pancreatic transplantation
[99, 100]. Octreotide (SMS 201-995) was synthesized to
be more specific, more potent and have longer-acting
inhibitory effects than native somatostatin [101–103]. In
particular, the longer half-life of octreotide (100 min) in
comparison to somatostatin-14 (2–3 min) has made this
compound preferable for clinical application. Octreotide
can be given three times daily due to its biological action
of 8–10 h. In a pilot trial, we were able to show that 100 Ìg
of octreotide administered subcutaneously inhibited the
stimulated secretion of amylase, trypsin, and chymotrypsin by 84, 76 and 77%, respectively [104, 105]. Our data
confirmed those of earlier reports which showed a maximum inhibition of pancreatic protease and amylase secretion with comparable dosages of octreotide.
In multicentric, placebo-controlled, double-blind studies carried out in Germany by our group [23], and in two
studies in Italy [29, 31] and one in France [27] using a
comparable study design, the ability of octreotide to prevent complications in pancreatic cancer patients undergoing major pancreatic surgery was investigated. Recently,
Complications in Pancreatic Cancer
Surgery
two additional prospective, randomized trials have addressed this topic: a small single-institution trial in Spain
and one in the USA [28, 32]. In all five multicenter studies
and in the small Spanish single-institution trial, the postoperative complication rate was significantly lower in
patients with octreotide treatment than in patients who
received a placebo. Only in the American single-institution trial was there no difference in the postoperative
complication rate.
There were several important differences between the
multicentric studies and the US study. In the former,
octreotide was administered before the operation; in the
latter it was delayed until either the reconstruction was
finished or the entire operation was complete. This means
that octreotide was not given prophylactically. However,
octreotide is supposed to inhibit pancreatic secretion and
thereby remove tension from the pancreatic anastomosis.
In this way, the pancreatic anastomosis can heal faster,
and hopefully postoperative complications will be reduced. To achieve this effect, octreotide must be administered before the anastomosis is performed.
Another difference was the postoperative observation
time: only 30 days in the US trial compared to 90 days in
the other studies. Also, since most of the patients enrolled
in the US study received preoperative chemoradiation,
the pancreas could have had a firmer texture (fibrosis)
than is usual in pancreatic cancer, with subsequently
decreased pancreatic exocrine function. Therefore, most
of the patients in this study may actually have belonged to
a low-risk group according to the definitions set out in the
German trial. A much higher number of patients is
required to prove the efficacy of octreotide in preventing
postoperative complications, as was shown in studies
enrolling patients with chronic pancreatitis. Furthermore,
the American study was not double-blind or placebo-controlled. This is, in our opinion, a major flaw in the study.
It is well known that the bias of an investigator has a
major influence on the outcome of a study.
In summary, the perioperative administration of the
somatostatin analogue octreotide reduces the occurrence
of typical postoperative complications in patients undergoing elective pancreatic surgery for pancreatic or periampullary cancer.
Dig Surg 1999;16:327–336
333
Conclusions
Pancreaticoduodenectomy is still a demanding procedure; it can nowadays be performed with low operative
mortality, but postoperative complications are still a common problem. With a proper surgical technique, devastating postoperative complications such as leakage of the
pancreaticointestinal anastomosis and hemorrhage can be
avoided. For the anastomosis with the pancreatic remnant we perform an end-to-side, duct-to-mucosa pancreaticojejunostomy. However, probably the gentle handling
of the soft pancreatic tissue is more important than the
technique used. Several randomized, placebo-controlled,
multicenter clinical trials have proven that prophylactic
perioperative application of octreotide (3 ! 100 Ìg/day
s.c. for 7 days) reduces postoperative complications in
resective pancreatic cancer surgery.
There is increasing evidence that pylorus-preserving
Whipple resection provides better long-term results with
regard to quality of life than the classical Whipple resection without compromising onclogical radicality. Therefore, it should be the standard operation for pancreatic
head and periampullary malignancies in the future. Extended radical pancreaticoduodenectomy with retroperitoneal lymphadenectomy can be performed without increasing morbidity in specialized centers. However,
whether it provides survival benefits in pancreatic cancer
has to be proven in future studies.
Pancreaticoduodenectomy is still one of the ‘Cadillacs’
in general surgery but in specialized hands it can be performed safely with low perioperative mortality and morbidity. In specialized centers, where clinicians are able
also to diagnose and treat major postoperative complications such as leakage of the pancreaticointestinal anastomosis, fistulae, abscesses and hemorrhage promptly and
appropriately, this operation represents the only option
for cure or good palliation for patients with pancreatic
cancer.
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