The Determinant Factors of Recurrence

Giuliano Barugola, Massimo Falconi, Rossella Bettini, Letizia Boninsegna, Andrea Casarotto,
Roberto Salvia, Claudio Bassi, Paolo Pederzoli
‘B’ Unit, Department of Surgery, University of Verona. Verona, Italy
Summary
Long-term survival for patients with
pancreatic carcinoma is low, even following
resection. Most patients who undergo curative
treatment, develop recurrence usually at the
same site of resection or in the liver. Failure
seals the fate of the patient. Local recurrence
occurs frequently; however, it is rarely a
direct cause of death. In fact, most patients
die from distant metastases. From a clinical
point of view, it is important to distinguish
recurrence from relapse. In fact, recurrence
can be recognized as the reappearance of the
disease in the surgical bed, often due to
inadequate surgical clearance. On the other
hand, the concept of relapse should be much
more related to the appearance of the disease
in a distant site. Both underestimated staging
of the diagnosis and the biological features of
the tumor can cause relapse.
Up to now, there have only been a few
reviews on the incidence and pattern of failure
following resection. Detailed knowledge of
the recurring sites of pancreatic carcinoma
and study of the factors influencing disease-
free survival are significant in developing
neoadjuvant, surgical and adjuvant treatment.
The aim of this review is to point out the
major factors most commonly identified as
determinants of both recurrence and relapse.
Introduction
The overall prognosis of pancreatic cancer is
poor, due to the low rate of resectability and
the aggressiveness of the disease itself. In any
Table 1. Patterns of failure following pancreatic resection for cancer in published series.
Author
No. of patients
Recurrence
Local
Hepatic
Griffin et al., 1990 [44]
36
72%
27%
15%
Hiraoka et al., 1990 [45]
51
84%
N/a
N/a
Westerdahl et al., 1993 [15]
86
86%
8%
14%
Kayahara et al., 1993 [41]
45
67%
33%
10%
Takahashi et al., 1995 [46] a
25
N/a
100%
80%
Nitecki et al., 1995 [47]
169
66%
25%
37.5%
Sperti et al., 1997 [8]
88
77%
33%
24%
Hishinuma et al., 2006 [3] a
27
92%
75%
50%
autopsy findings
N/a: not available

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case, following resection, the 5-year survival
rate of patients ranges from 10 to 25% [1, 2].
In fact, despite the application of an
apparently curative surgery, the disease
usually recurs. Ninety-five percent of tumor
relapses occur within 2 years from the
resection and the most common sites of
failure (97%) are intra-abdominal. These
include the local-regional area, the liver and
the peritoneal cavity (Table 1). Failure seals
the fate of the patient. In fact, neither curative
surgery nor antitumoral therapies can cure the
disease. Local recurrence occurs frequently;
however, it is rarely a direct cause of death
since most patients die from metastases [3].
The site and incidence of failure depend on
different aspects. From a clinical point of
view, it is important to distinguish recurrence
from relapse. In fact, recurrence can be
recognized as the reappearance of the disease
in the surgical bed (nodes and surgical
margins), often due to inadequate surgical
clearance. On the other hand, the concept of
relapse should be much more related to the
appearance of the disease in a distant site.
Both underestimated staging of the diagnosis
and the biological features of the tumor can
cause relapse. Because of this, pancreatic
ductal cancer must be taken into consideration
as a systemic disease right from the
beginning. However, although many
antecedent studies have been focused on the
identification of these factors, they were only
associated with a poor survival rate. On the
other hand, there is a close relationship
between poor survival rate and early death. In
fact, the average survival length between the
detection of local recurrence and death is 7
months. However, the average survival length
in patients with hepatic recurrence is 3
months [4].
In any case, the surgeon’s role is of primary
importance since he is responsible for
deciding both the indications to surgery and
the intra-operative surgical management.
The aim of this review is to point out the
major factors most commonly identified as
determinants of both recurrence and relapse.
Understanding these factors is of fundamental
importance together with the decision for
surgery. These can be assessed and might
differentiate according to three different
aspects: preoperative, intra-operative and
post-operative periods.
Pre-Operative Period
Once imaging has determined that a ductal
cancer is resectable, the most common
laboratory and clinical data associated with
the post-resectional failure are CA 19-9, pain
and hyperamylasemia.
CA 19-9
Before resection for ductal carcinoma, CA 19-
9 can be considered the most important
predictive factor of both recurrence and
survival. It has been suggested that tumor
cells expressing CA 19-9 have a higher
degree of adhesion to endothelial cells in the
process of metastasis. This seems to be due to
its role in endothelial leukocyte adhesion
molecule-1 mediated binding between human
cancer cells and activated endothelial cells
[5]. This evidence can explain the positive
correlation reported in the literature between
the expression of CA 19-9 and the hepatic
metastatic potential of pancreatic cancer [6].
Furthermore, there is a direct relationship
between tumor burden and CA 19-9 level [7].
In fact, serum CA 19-9 levels significantly
correlate with the systemic spread, its
dimension and its local diffusion.
Various data suggest that CA 19-9 is a useful
tool for the management of patients with
regard to planning the resection. Patients with
a preoperative serum marker of less than 200
U/mL have an average survival rate of 22
months as compared to 8 months for those
with a preoperative serum level greater than
200 U/mL [8, 9, 10]. More recently, findings
have demonstrated that, although preoperative
CA 19-9 levels do not predict a pathological
stage in an absolute way, their higher values
should raise suspicion of a more extensive
tumor burden and a more advanced stage,
with an indicative cut-off of 163 U/mL in
non-jaundiced patients [11].

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In general, patients with a high level of
preoperative CA 19-9 and apparently
resectable tumors could be suitable for a neo-
adjuvant approach. However, there are two
main limiting factors. First of all, almost 10%
of the population do not express the marker
due to the lack of the Lewis factor (a)/(b)
even in the presence of a pancreatic
carcinoma. Secondly, neoplasms which have
been poorly differentiated do not express this
antigen to a relevant extent [12].
Hyperamylasemia and Pain
Abdominal and/or back pain have been found
to be a positive prognostic factor in many
multivariate analyses. This may be due to the
occurrence of pancreatitis or tumoral invasion
of the retroperitoneal nerves.
Preoperative serum amylase has also been
recognized as another prognostic factor of
survival. These findings suggest that an
inflammation caused by the obstruction of the
main pancreatic duct and its branches could
promote a rapid tumor progression. The
possible relationship between inflammation
and cancer has been described for several
gastrointestinal cancers [6, 13, 14]. Recently,
some authors have reported that the human
pancreatic cancer cell line, Capan-1,
expresses chemokine receptor 2, which is an
interleukin 8 receptor. IL-8 might contribute
to the tumor progression via NF-kappa B
activation, since IL-8 activates NF-kappa B.
Furthermore, the expression of the
downstream genes of NF-Kappa B, such as
urokinase plasminogen activator, are
significant in cancer metastasis [5].
Additionally, pancreatitis also promotes the
increase of serine protease levels in the
pancreatic blood. This data also supports the
hypothesis of a strong correlation between
inflammation and tumor progression.
During clinical intercourse, multivariate
analysis identified hyperamylasemia and
abdominal pain as prognostic factors of early
mortality and high hazard rates closely linked
with death from liver metastasis in the early
postoperative period [5].
Intra-Operative Period
The types of operation, the extension of the
lymphadenectomy and intra-operative
radiotherapy (IORT) are factors considered by
many papers to affect both survival and
recurrence.
Type of Operation
It is obvious that any treatment aiming at a
cure must include surgical removal of the
tumor as its main modality. Despite the initial
expectation was that a complete
pancreatectomy would be more successful
than a subtotal pancreatectomy with regard to
survival and recurrence, this has not been the
case [15, 16]. As to subtotal procedures, the
pylorus-preserving pancreaticoduodenectomy
as compared to the classical Whipple is to be
considered more successful with regard to
metabolic function, hormonal regulation and
quality of life. Furthermore, there is no
significant difference in oncological
radicality, survival, type and incidence of
recurrence [17, 18, 19]. This evidence
suggests that the real determinant in the
operating theatre is not the type of resection
but its correct execution; in fact, pancreatic
resections performed in teaching hospital are
associated with a significantly higher survival
rate [17].
Type of Lymphadenectomy
Once established that a long survival rate can
not be guaranteed by pancreatic resection
alone, many authors have suggested
associating resection with an extended
lymphadenectomy in order to improve long-
term disease-free survival. However,
consecutive randomized controlled studies
have not confirmed this benefit [20, 21, 22,
23]. Four randomized controlled trials, which
included more than 500 patients, essentially
report that an extended lymphadenectomy
does not offer a higher survival rate as
compared to a standard procedure and that it
also potentially compromises safety and
quality of life [2] (Table 2).

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Furthermore, there is no significant difference
in the disease-occurring site in both extended
and standard lymphadenectomy procedures.
In fact, hepatic failure seems to be more
related to the surgical characteristics of a
lymphadenectomy than with its surgical
extension. However, in clinical practice, no
doubts exist that an inadequate
lymphadenectomy leads to a high local
recurrence rate. In this setting, it has been
accepted that at least 15 nodes should be
removed
along
with
a
pancreaticoduodenectomy (see section Post-
Operative Period: Node Factor).
Intraoperative Radiotherapy (IORT)
Intraoperative radiotherapy is a practice
which allows the irradiation of tissues
surrounding the malignant cells at the time of
surgery. IORT is considered to be an adjuvant
treatment of the pancreatic bed at the time of
resection to reduce the incidence of local
recurrence. IORT appears to have the benefit
of improving local disease management
without modifying the total survival rate [24].
This is due to its inefficacy in reducing the
incidence of widespread metastases. In any
case, in the absence of any definitive
evidence, a sequential external beam course
of radiotherapy should be suggested after
IORT.
Post-Operative Period
Once the surgeon has satisfactorily removed
the tumor at the macroscopic level, the
histopathological features of the neoplasm
and serum concentration of CA 19-9 can help
in planning the follow-up and adjuvant
treatment.
CA 19-9
CA 19-9 also has a great relevance as a
prognostic factor in the postoperative period;
in multivariate analysis, a high CA 19-9
serum level after surgery (greater than than
200 U/mL) correlates with early mortality,
with a higher T stage and positive lymph
nodes [11].
Following curative resection, a significant fall
in serum CA 19-9 is expected within 15 days;
when the resection is not followed by an
immediate decrease in value, the prognosis is
poor [7]. This situation is due to both
inadequate surgical clearance and to
underestimated staging of the disease. On the
other hand, a secondary increase in the serum
concentration develops, after its initial
normalization during the follow up, is more
likely to be connected to the biological
aggressiveness of the tumor. This secondary
increase precedes the imaging confirmation of
failure by 2 to 9 months. This aspect can be
demonstrated by a linear correlation in the
analysis of Fuzhou et al. between survival and
a doubling of the CA 19-9 time prior to death
[7]. The average time between surgery and
radiological detection of tumor recurrence
was significantly longer in patients with
normal postoperative CA 19-9 values than in
patients with persistently abnormal values [8,
11]. Due to the above reasons, the CA 19-9
value in patients who underwent resection is a
useful tool in predicating tumor recurrence
before clinical and radiological appearance
[7].
Table 2. Controlled randomized clinical trials on standard versus extended lymphadenectomy in patients resected for
pancreatic cancer.
Author
No. of patients
Morbidity
Survival
Pedrazzoli et al. 1998 [23]
81
No difference
No difference
Yeo et al. 2002 [21]; Yeo, et al. 2005 [48]
167
Extended > standard
No difference
Nimura et al. 2004 [49]
101
Extended > standard
No difference
Farnell et al. 2005 [20]
79
Extended > standard
No difference

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Margin Status Factor
The R classification is one of the most valid
predictive tools of the outcome. The correct
surgical resection margins of a
pancreaticoduodenectomy
have
been
considered to be the transaction line of the
stomach or the duodenum, the pancreas and
the distal bile duct.
The evident hot-spot of surgical resection and
histopathological examination is the
retroperitoneal margin adjacent to the
proximal 3-4 cm of the superior mesenteric
artery. Microscopically incomplete resection
could result due to three factors:
• poor patient selection, lack of quality pre-
surgical imaging;
• surgeon failure to separate the specimen
from the retroperitoneum in the immediate
peri-adventitial plane of the superior
mesenteric artery;
• infiltrative nature of the adenocarcinoma
of the pancreas, expression of biological
aggressiveness.
Traditionally, only the microscopically
completed resection of the primary tumor
offers a chance of cure for patients with
pancreatic cancer [15]. Patients with positive
resection margins (R1) following the
operation are associated with a lower survival
rate than those with clear resection margins
(R0) [25, 26]. Although it was claimed that
pancreatic R0 resection reduces the rate of
local recurrence, there is no significant
difference in the total survival rate between
R0 versus R1 resection. This fact is confirmed
by similar early hepatic recurrence in both
groups. The early development of liver
metastases following radical resection
supports the hypothesis that hidden
microscopic liver metastasis are present at the
time of resection. However, studies
addressing this point are still lacking.
When the surgeon in the operating theatre
becomes aware that clean margins were not
obtainable (R2), although the tumor was
resected with curative intention, the resection
will be considered only a palliative treatment.
Therefore, this group of patients is
characterized by the progression of the
disease only, without recurrence.
Node Factor
Lymph node positive patients have a 5-year
survival of 8% after resection compared with
40% of those who are lymph node negative;
traditionally, positive node status is primarily
thought to carry prognostic importance but
not therapeutic relevance [27, 28].
Analyzing the pattern of recurrence and
factors predicting survival after pancreatic
resection, lymph node metastasis is one of the
most significant predictor factors in univariate
and multivariate analysis [11, 21, 29, 30, 31,
32].
Recent reports have identified a relationship
between the number of lymph nodes
examined and their value as a separate
prognostic factor in many malignancies;
however, in pancreatic resection, the number
of lymph nodes gathered during pancreatic
resection has no impact on overall survival
and disease-free survival rates [33].
Although the mechanism remains unclear and
could reflect confounding factors (R status),
an attempt to resect and examine at least 15
lymph nodes seems sensible for curative-
intent pancreatectomy and useful for defining
the cut-off stage of N0 [27].
Adjuvant Therapy
Many studies have investigated the effects of
adjuvant therapy on survival and recurrence
of disease. Among those, the largest is the
ESPAC-1 study which demonstrated a
significant result of survival rate from
adjuvant chemotherapy with 5-fluorouracil
associated with folinic acid as compared to
chemoradiation and to non-application of
therapy, without specificity about incidence
and site of recurrence [34, 35]. A similar
result has been observed with gemcitabine
with a significant reduction of toxic, therapy-
related effects [36]. IORT, as we have just
analyzed, does not seem to have any survival
advantage over conventional postoperative

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radiotherapy. The inefficacy of irradiation by
itself with regard to the survival rate must be
considered with its target. In fact,
radiotherapy offers a control of local
recurrence without any significant benefit on
hepatic failure, which is a real determinant for
a low survival rate.
A clinical trial used prophylactic hepatic
irradiation (PHI) to reduce hepatic failure
after resection. The cumulative incidence of
liver metastasis was significantly lower for
the PHI group than the non-PHI group.
Patients in the PHI group also survived
significantly longer as compared to those in
the non-PHI group [37, 38]. Although this
study suggests that PHI may reduce the
frequency of hepatic metastases, the
complications of high-doses related to the
treatment and the failure of controlling both
the primary tumor and intra-abdominal spread
remain overwhelming.
In a recent study, resection was followed by
interferon-based
chemoradiation
with
encouraging results [39].
Grading Factor
The histological grade of the tumor was also a
significant predictor of the outcome. Patients
with a well-differentiated tumor had
significantly higher survival rates than those
with moderately or poorly differentiated
tumors. However, the rates of survival
between patients with G2 and G3 tumors were
not significantly different [17] (Table 3).
Undifferentiated adenocarcinoma is a strong
predictor of poor outcome since it is related to
hepatic metastases [40].
Macroscopic Features
The relationship between several clinical and
pathologic features correlates with the
incidence of recurrence and the tumor spread.
The recurrence rate for T2a tumors was
significantly lower than for T2b tumors.
Moreover, the recurrence rates for patients
with serosal invasion were significantly
higher than those for patients without
invasion [41].
A tumor with a diameter larger than 15-20
mm can be associated with a low survival rate
and early failure [17, 42]; however, there is
no evidence about incidence and site of
recurrence. Furthermore, tumor dimension
does not appear to be directly proportional to
its capacity of hepatic diffusion. In fact,
neoplasms less than 20 mm in diameter have
been thought to be capable of determining
abdominal failure [43].
Keywords Carcinoma, Pancreatic Ductal;
Pancreatic Neoplasms; Recurrence; Surgical
Procedures, Operative
Abbreviations
IORT: intra operative
radiotherapy; PHI: prophylactic hepatic
irradiation
Conflict of interest The authors have no
potential conflicts of interest
Correspondence
Massimo Falconi
Chirurgia B
Policlinico “GB Rossi”
Piazzale LA Scuro
37134 Verona
Italy
Phone: +39-045.812.4553
Fax: +39-045.820.1294
E-mail: massimo.falconi@univr.it
Document URL: http://www.joplink.net/prev/200701/23.html
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P value
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P=0.01
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P=0.002a
Lim et al., 2003 [17]
88
P=0.04
De Castro et al., 2004 [29]
396
P=0.02a
Shibata et al., 2005 [40]
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P=0.001a
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