Surgical Advances in Pancreatic Cancer- Beat M. Künzli

Surgical Advances in Pancreatic Cancer
Beat M. Künzli, Jörg Kleeff, and Helmut Friess
Department of General Surgery, Klinikum rechts der Isar, Technische Universität
München, Munich, Germany.
Address for correspondence:
Jörg Kleeff, MD
Department of General Surgery
Klinikum rechts der Isar, Technische Universität München
Ismaningerstrasse 22
81675 München
Germany
Phone: +49 89 4140 5098
Fax:+49 89 4140 4870
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Introduction
Despite improvements in diagnosis and therapy, pancreatic cancer is still a devastating
disease, which is presently the fourth leading cause of cancer related deaths in Western
countries. 1 Although significant efforts have been made, only little progress has been
achieved in the last decades with respect to the overall survival of pancreatic cancer
patients. It is still a challenging task to diagnose pancreatic cancer at an early stage that
offers the chance of successful therapy. Thus, the overall resectability rate of pancreatic
cancer is only 10 to 15%. 2 Rapid tumor progression, and a striking resistance to
chemotherapy, radiotherapy, and targeted/biological therapies 3, 4 contribute to the poor
prognosis. These facts together result in low tumor resectability rates after diagnosis,
early tumor recurrence after resection, and poor overall survival rates. Even after
potential curative resection, long term survival is not satisfactory with around 20%, but
subgroup analyses of e.g. lymph node negative tumors that have been resected with
negative margins demonstrate 5-year survival rates of about 40%. 5 In the last decade
the surgical outcome has improved, mostly because of improving perioperative
treatment. Birkmeyer et al. 6 demonstrated that operation related morbidity and mortality
significantly decreases in centers with high patient load. This critical aspect of the value
of centralization on the outcome of pancreatic surgery in “high volume institutions,” has
been demonstrated in numerous studies. 7 The current mortality rate following pancreatic
resection is well below 5% 8 in specialized surgical centers. Improvements in multimodal
therapy 9 combined with more experienced surgical treatment of pancreatic cancer at
high volume centers have improved the long-term survival as well as the quality of life of
pancreatic cancer patients.
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Operations for tumors of the head of the pancreas
Periampullary cancers account for about 5% of all gastrointestinal tract malignancies, 10
which can be divided into four groups of tumor entities: (i) periampullary tumors that
originate from the pancreas (pancreatic cancer), (ii) the mucosa of the ampulla of Vateri
(ampullary carcinoma), (iii) the common distal bile duct (distal cholangiocellular
carcinoma) or (iv) the mucosa of the duodenum (duodenal adenocarcinoma). The most
common periampullary malignancy is pancreatic cancer, accounting for 3% of all
gastrointestinal tumors. Carcinoma of the ampulla of Vateri is the second most common
periampullary malignancy 11 . Distal cholangiocellular carcinoma is less frequent and
duodenal adenocarcinoma of the periampullary region is only rarely seen. 12 The
relatively poor prognosis for periampullary carcinomas, excluding pancreatic head
cancers, with five-year survival rates varying between 24 and 50%, still remains a
challenge. 12
One limitation for studies reporting on periampullary carcinomas, excluding pancreatic
cancer is that these studies contain only relatively small numbers of study subjects. 11-13
Nevertheless, the standard therapy of choice for all entities of periampullary carcinomas
is a partial pancreatoduodenectomy (PD), irrespective of the underlying histology. 12
Despite their low incidence rates, ampullary, cholangiocellular, and duodenal cancers
are attracting attention due to their suspected diverse biological behavior leading to
improved survival rates in comparison to pancreatic cancer. 10, 12 In the next passages of
this chapter, we will focus on the therapy modalities for pancreatic cancer.
The majority of all pancreatic cancers (approximately 60%) arise in the head of the
pancreas. In these cases a partial pancreatoduodenectomy (classical Kausch-Whipple
procedure) or a pylorus preserving pancreatoduodenectomy is considered the gold
standard for surgical therapy. Cameron et al. 5 demonstrated in a retrospective review of
1000 pancreaticoduodenectomies- performed by a single surgeon- the management and
outcome of these patients. The evolution of this operative procedure was also analyzed
over 5 decades, demonstrating a significant drop in median operative time and in the
postoperative hospital stay from initially 17 to 9 days. The mortality rate in this series
was 1%. The overall 5-year survival rate was 18%, for the lymph-node negative patients
it increased to 32% and for lymph-node negative patients with negative resection
margins it reached 41%. 5 This study demonstrates on the basis of a large patient
3

population, how the improvements in surgery as well as advances in peri and
postoperative care can increase the long term survival rates of patients with pancreatic
cancer treated by pancreatoduodenectomy. This operation has become safe and
effective, with low hospital mortality rates. The question which type of the
pancreatoduodenectomy suits best has been controversially discussed. However,
several randomized controlled studies have been performed, comparing the classical
Kausch-Whipple with the pylorus-preserving pancreatoduodenectomy.
Classical Kausch-Whipple vs. pylorus preserving pancreatoduodenectomy (PD)
The classical procedure for operating on pancreatic head masses was the Kausch-
Whipple operation that consists of the resection of the pancreatic head, the duodenum
along with a distal gastrectomy, cholecystectomy, removal of the distal common bile duct
segment, proximal jejunum, and en-bloc resection of regional lymph nodes. With the reintroduction
of the pylorus-preserving pancreaticoduodenectomy, a modified procedure
without resection of the pylorus and the distal part of the stomach, a controversial debate
on what should be the standard pancreatic head resection had started early. 14 Initial
studies reported a higher incidence of complications, such as delayed gastric emptying
and concerns about less oncological effectiveness of the pylorus-preserving procedure.
Meanwhile, randomized controlled trials as well as a meta-analysis have demonstrated
that both perioperative morbidity and long-term outcome are equal for the classical
Kausch-Whipple and the pylorus preserving PD. 15, 16 Even though the question which
procedure should be performed for pancreatic head cancer is not definitively answered,
both procedures can be recommended for resection of cancer arising in the head of the
pancreas, according to the most recent available data.
Distal pancreatectomy
Tumors that arise in the body or tail of the pancreas can be operated with a distal
pancreatectomy. The distal pancreatectomy consists of the removal of the portion of the
pancreas extending to the left of the midline but does not include resection of the
duodenum and the distal bile duct. The advantage of this procedure, compared to the
PD procedure, is that a pancreatic anastomosis is not needed in most cases. Therefore
the distal pancreatectomy has been considered as a simpler surgical procedure in
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comparison to a pancreaticoduodenectomy. However, pancreatic fistulas occur in 10-
20% of cases and result in increased postoperative morbidity, length of hospital stay,
and overall costs. 17 In a recent retrospective study, stapler closure of the pancreatic
remnant has been reported to be associated with significantly higher fistula rates. 18
Therefore, randomized controlled trials have been initiated to identify the best technique
for closure of the pancreatic stump.
Another important aspect of distal pancreatectomy is the often concomitantly performed
splenectomy. Schwarz et al. 19 showed that the median survival of patients undergoing
distal pancreatectomy with curative intention for pancreatic cancer was 17.8 months
without splenectomy and 12.2 months with splenectomy. The en-bloc resection the
spleen was believed to be necessary due to regional lymph nodes and the close relation
of the splenic artery and vein to the body of the pancreas. Hence, splenic preservation
was thought to compromise the oncological resection. Schwarz et al. recommended
therefore that the spleen should be preserved unless the splenic capsule was directly
involved, or nodal clearance required a splenectomy. 19
Total pancreatectomy
In order to improve postoperative outcome, the radical total pancreatectomy has been
introduced to the treatment of pancreatic head cancer. Obviously, this more radical
approach with resecting the whole gland would include the elimination of multifocal
disease and complications emanating from the pancreatic remnant (e.g. pancreatic
fistula). Furthermore, the additional resection of the body and tail of the pancreas would
increase the possibilities for a more extensive lymphadenectomy around the body and
tail of the pancreas as well as tumor resection adjacent to the retroperitoneum. However,
recent studies revealed that the occurrence of multicentric pancreatic cancer is fairly
uncommon, occurring in less than 10% of cases. 20 Moreover, randomized trials on
extended lymphadenectomy showed no significant oncological benefits, especially
because lymph nodes around the body and tail of the gland are rarely involved with
metastatic disease from pancreatic head cancer. In contrast, the removal of the entire
pancreas results in severe endocrine and exocrine insufficiency. In terms of studies,
Muller et al. 21 reported that total pancreatectomy had a surgical morbidity of 24% and an
overall mortality rate of 4.8%. The global health status of patients, that have undergone
a total pancreatectomy was after 23 months comparable to that of pylorus preserving
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pancreatoduodenectomies, although quality of life (QoL) was reduced. They concluded,
that total pancreatectomy can be a treatment option for selected patients. 21 In
conclusion, total pancreatectomy should not be performed routinely for pancreatic head
cancer. Rare exceptions may include tumor extension to the body/ tail of the pancreas
and the presence of an atrophic, soft and friable pancreatic parenchyma for which an
anastomosis is not considered safe.
Venous resection
The specific anatomic position in close proximity to the portal vein, the celiac trunk,
superior mesenteric vessels, combined with the extensive and aggressive growth
behavior predisposes pancreatic carcinoma to affect or even infiltrate these structures.
Therefore venous resections were suggested in order to obtain complete tumor
resections and avoid R1 or even R2 resections. Recent studies indicate that venous
resections can be performed without increased morbidity and mortality. 22 However, data
on long-term survival after venous resection are less clear. A recent systematic review
on portal vein resection reported a median survival of only 13 months following
resection. In this study patients were treated from 1965 to 2003 and positive resection
margins occurred in about 40% of cases. 23 Better survival rates have been
demonstrated in some single center studies. 22 Irrespectively, numerous studies have
shown that partial resection of the portal vein/superior mesenteric vein can be carried
out safely, without the risk of increased morbidity/mortality. In addition, a randomized
multicenter trial comparing resection and radiochemotherapy for locally resectable
invasive pancreatic cancer reported a median survival of >17 months in the surgically
treated group versus 11 months in the radiochemotherapy arm. 24 These studies together
demonstrate that venous infiltration should not be considered a contraindication for
resection in pancreatic cancer if a potential curative resection can be achieved. This
strategy has also been adopted in current guidelines in the USA as well as in Europe.
Extended lymphadenectomy
Attempts have been made to decrease the high local recurrence rate following
pancreatic cancer resection by performing a more radical lymph-node dissection. The
rationale for this approach was the observation of affected lymph nodes in the paraaortic
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egion encapsulated between the celiac trunk and the origin of the superior mesenteric
artery. 25 Therefore, the idea to radically operate and remove all these lymph- nodes
seemed to be an appropriate approach. Indeed, initial retrospective studies on extended
radical lymphadenectomy in cancer of the pancreatic head reported a survival benefit in
comparison to standard resection. 26 However randomized controlled trials revealed
different result. In fact, overall morbidity with diarrhea and delayed gastric emptying
tended to occur more frequently after extended lymphadenectomy. A study by Yeo et al.
27
demonstrated comparable mortality and survival rates, whereas morbidity was
significantly increased in the extended lymphadenectomy group with increased rates of
postoperative diarrhea and resulting malnutrition. 28 This study failed to report differences
in 1, 3, and 5-year survival rates. 28 A meta-analysis of standard and extended
lymphadenectomy in pancreaticoduodenectomy for pancreatic cancer including three of
four randomized controlled trials confirmed the data from Yeo et al. 27 and Farnell et al. 28
indicating no significant differences between the standard and extended procedure. 29
There were no differences in morbidity and mortality rates, with a trend towards higher
incidence of delayed gastric emptying for extended lymphadenectomy. 29 Although the
available randomized studies are underpowered and lack clinical standardization
regarding the extent of lymphadenectomy, adequate randomized controlled trials that
would be needed to determine any potential survival benefit, are highly impractical.
Therefore, extended radical lymphadenectomy should not be performed routinely.
Does R1 resection limits surgical practice?
A key factor for long- term survival of patients with resected pancreatic cancer is a
complete tumor resection with negative resection margins (R0 resection). Although R0
resection rates have been reported in up to 75% in large surgical series, most patients
develop local and/or distant recurrences which could be caused by microscopic residual
disease (R1 resection) at the time of resection. Using new standardized pathological
processing techniques and protocols, a recent study by Esposito et al. 30 displayed R1
resection rates for pancreatic cancer of up to 76%. The most common anatomical site
for evidence of tumor remnants was the posterior margin. In contrast, the R1 resection
rate was 14% (carried out by the same team of surgeons) when no standardized
protocol was used. 30 These results demonstrate the particular need of a thorough and
standardized pathological examination of pancreatic cancer specimen, in order to allow
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a precise investigation and definition of prognostic relevant histopathological markers.
Furthermore, these data finally influence the decision making with respect to therapeutic
options such as adjuvant therapy.
Conclusion
In the last decades major pancreatic operations have evolved into safe and standard
surgical procedures. Most progress has been made in peri and postoperative practices
and treatment modalities. Therefore, in high-volume centers, surgery for pancreatic
cancer is safe with morbidity and mortality rates that are not different from other major
gastrointestinal surgeries. The 5-year survival has increased to 15%- 25% following
resection of pancreatic cancer. However, the notable breakthrough has not yet come
and the overall prognosis of pancreatic cancer has barely changed over the years.
Future studies and potentially multimodal therapies are being established in order to
improve long- term survival of pancreatic cancer patients. Adjuvant chemotherapy with
either 5-FU or gemcitabine has been shown to improve prognosis in resectable
pancreatic cancer. Combinations of chemoradiation and interferon- α as well as novel
biological therapies present promising future perspectives in the treatment of pancreatic
cancer. Extensive surgery should be critically evaluated, extensive/radical
lymphadenectomy has not shown to improve prognosis; however, an isolated portal vein
involvement on the other hand does not represent a contraindication for tumor resection.
More extensive surgery on metastatic 31 and recurrent disease 32 remains questionable,
although some studies seem promising.
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