Editorial
Highlights in Pancreatic Carcinoma
Patrone R, Gambardella C, Di Capua F, Offi C, Clarzia G, Andretta C, De Vita F, Tirino G, Orditura
M, Romano M, Santini L and Conzo G*
Department of General and Oncological Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy
*Corresponding author: Giovanni Conzo, Department of General and Oncological Surgery, University of Campania "Luigi Vanvitelli", Ed. 17 via S. Pansini 5, 80131 Naples, Italy
Published: 10 Oct, 2017
Cite this article as: Patrone R, Gambardella C, Di Capua
F, Offi C, Clarzia G, Andretta C, et al.
Highlights in Pancreatic Carcinoma.
Clin Surg. 2017; 2: 1655.
Editorial
Pancreatic cancer is a malignant tumor with poor prognosis. In the Western World, during the
lasting two decades, a surprising increase of incidence and cancer related mortality was observed,
despite significant progress in terms of early diagnosis and treatment. In Italy the peak of incidence
is registered between the sixth and the fifth decade of life and it represents the fifth leading cause
of cancer death in males and fourth one in females and five years survival is less than 10% [1].
Despite medical progress, there are no mass screening procedures but closers monitoring could
be performed for high-risk subjects. The risk factors associated with pancreatic cancer are still not
defined although few studies show some reliable data [2,3]. Smokers have a triplicate risk of incidence
than no-smoking (relative risk: 1.74) and smoking cessation results in a risk decrease because
nitrates induce inactivating mutations of the K-ras. Obesity is the second most important risk factor
for the development of pancreatic cancer [4]: a high body mass index (BMI> 30kg/m2) is associated
with greater risk of death from pancreatic cancer by 20% to 40% [5]. Other related conditions with
pancreatic cancer are diabetes mellitus type 1 and 2 and chronic pancreatitis [6]. Regarding genetics,
10% of patients with pancreatic tumors present a genetic predisposition [7,8]. The most important
mutated genes involved are FANCA [9,10], BRCA2 [11], PALB2 [12], PRSS1 [13], SPINK1 [13],
STK11/LKB1 [14], CDKN2A [15], MSH2 and MLH1 [16]. Recently in USA a screening program
for high-risk people, by endoscopic ultrasound, able to identify 10% of pancreatic cancer at preinvasive
stage has been described [17]. Diagnoses and resectability criteria are obtained after the
evaluation of several factors. Nowadays, the multi-slice CT is the best method for both diagnosis and
staging: pre-contrast study allows excluding the presence of calcifications and allowing obtaining
a differential diagnosis with chronic pancreatitis [18]. CT abdomen +/- MRI offers high levels of
sensitivity in the differential diagnosis of adenocarcinoma (89% to 97%) assessing the unresectable
tumors (89% to 100%) in patients with pancreatic suspicious lesion [19]. Abdominal Ultrasound
(US) with color Doppler is the first step in preoperative evaluation. Color Doppler has 84% accuracy
for identification of porto-mesenteric axis invasion and 87% for evaluation of the arterial infiltration
[20]. US are a complementary technique to CT and MRI in the pancreatic cancer study and it is
useful to differentiate between benign and malignant disease [21,22]. According to several studies
MRI is still the best diagnostic tool in pancreatic diseases [23]. PET-CT is indicated for study of
metastatic disease to evaluate complete remission, recurrent disease and for differential diagnosis
between postoperative or post radiotherapy scar tissue [24]. CA 19.9 is the most useful tumor
marker for diagnosis of pancreatic cancer. The data about the predictive value in patients with
advanced disease are conflicting [25,26], while it appears to have a value as a prognostic survival
marker when blood levels of CA 19.9 decrease postoperatively [27-33] (Table 1). Pancreatic head
carcinomas are sub classified in pancreatic carcinomas, ampullary carcinoma, and carcinoma of the
lower third of the bile duct and periampullary carcinomas, the last with best prognosis [34]. In case
of malignancy suspicion a correct histological diagnosis fine needle aspiration under ultrasound
guidance, or true-cut biopsy, can be useful but is not mandatory. Cytology on fine needle aspiration
has a sensitivity and specificity of 69% and 100% for tissue diagnosis, respectively. A histological
or cytological intraoperative biopsy should be performed when an inoperable tumor is identified.
Tumor grading, anatomical origin, evaluation of surgical resection margins and evaluation of lymph
node involvement are the most important parameters with influence on the overall prognosis. The
grading of pancreatic cancer is based on WHO histopathological criteria and it is an independent
prognostic indicator. The evaluation of surgical resection margins in pancreaticoduodenectomy
includes the margin of the bile duct resection, pancreatic transection with the Wirsung duct and
gastroduodenal margins. For standardized evaluation of resection margins, is used R classification
(residual tumor): Rx (cannot be defined the presence of residual tumor); R0 (no residual macroscopic
and microscopic tumor); R1 (microscopically residual tumors are detected); R2 (macroscopic
residual) [35]. Although, given the discrepancy between several international guidelines, it is very hard to standardize recommendations. Classification and staging
systems reported by WHO in 2010 [36-38] and the TNM/AJCC 2009
[39] should be considered as cornerstones. Lymphnode involvement
is a paramount prognostic factor and removal of 12-15 lymph nodes
is considered oncologically adequate.
TNM system
Primary tumor
Tx: The primary tumor cannot be defined
T0: No evidence of primary tumor
Tis: carcinoma in situ, including PanIN-3 (Pancreatic
Intraepithelial Neoplasia)
T1: tumor limited to the pancreas, 2 cm or less in diameter greater
T2: tumor limited to the pancreas, more than 2 cm in greatest
diameter
T3: tumor extends beyond the pancreas without involvement of
the celiac axis or superior mesenteric artery
T4: tumor involving the celiac axis or the mesenteric artery
Regional lymph nodes
Nx: regional lymph nodes cannot be assessed
N0: no metastases to regional lymph nodes
Distant metastasis
Mx: the presence of distant metastasis cannot be defined
M0: no distant metastasis
M1: presence of distant metastases
Staging
Stage 0: TisN0M0
Stage IA: T1N0M0
Stage IB: T2N0M0
Stage IIA: T3N0M0
Stage IIB: T1-3N1M0
Stage III: T4 any NM0
Stage IV: any T any N M1
Surgery is the only curative treatment for pancreatic
adenocarcinoma [40,41], but unfortunately only 20% of patients
with pancreatic carcinoma has a resectable disease and the overall
survival does not exceed 20% [42,43]. In case of distant metastases
or infiltration of adjacent viscera - with the exception of biliary
tract and duodenum - surgery is contraindicated, while lymph node
involvement or mesenteric arteries (celiac, superior mesenteric
artery, hepatic artery) and main venous trunks infiltration might
considered as relative criteria of unresecability. According to most
recent scientific literature, the disease is considered borderline in
case of adhesion or infiltration <180º of the spleno-porto-mesenteric
venous axis with the possibility of tangential resection or full channel
resection and reconstruction. The disease is locally advanced when
the infiltration is >180º and/or in case of occlusion of spleno-portmesenteric
venous axis and/or presence of portal vein thrombosis
and/or infiltration of the celiac, superior mesenteric artery, hepatic
artery, vein inferior vena cava, aorta [44]. A meta-analysis has shown
that arterial resections were encumbered by an increased risk of postoperatory
mortality and a worse survival at 1 year and 3 years [45].
The same fate has also been reported in patients who have experienced
a venous resection [46]. Therefore, the debate is open and in patients
with "borderline resectable" cancer or at high risk of incomplete
resection according to pre-operative imaging a neoadjuvant
approach is the cornerstone of a multidisciplinary treatment [47,48].
In addition, according to several authors’ symptoms lasting more
than 40 days, the value of CA 19.9> 200 U/mL, the presence of a
poorly differentiated tumor (G3/G4) and R2 resection should be
considered as independent factors associated with early mortality
after surgical resection [49]. In particular, the presence of symptoms
lasting >40 days, CA 19.9 >200 U/mL and a G3/G4 tumor determine
a risk of mortality within 12 months after surgery equal to 60% for
resections R0, to 75% for R1 resection and to 90% for resections R2.
The presence of a poorly differentiated tumor is a negative factor in
terms of overall survival and disease-free survival [50,51]. In a series
of 169 patients undergoing surgical resection for resectable poorly
differentiated pancreatic cancer, the disease-free survival was 25% at
2 years and 14% at 5 years with a median of only nine months [53].
The same study showed that adjuvant treatment conferred a benefit
in terms of higher survival for G3 tumors compared to G1 and G2
forms. Radical surgery associated to lymphadenectomy is a golden
standard and might have a curative value.
Pancreaticoduodenectomy is the procedure of choice in the
treatment of pancreatic carcinoma of the head and uncinate process
and in addition a biliary drainage should be performed selectively
for patients presenting cholangitis or obstructive jaundice with
secondary renal impairment. Lymphadenectomy should also include
the peripancreatic stations with the hepatic and retroportal lymph
nodes [53]. The procedure is associated with a lower risk of mortality
in high-volume centers (5%) and with a risk of morbidity mainly
related to the development of postoperative pancreatic fistula [54].
Left splenopancreasectomy with lymphadenectomy of peripancreatic
stations is the treatment of choice for tumors of the body and tail
of the pancreas [55,56]. In addition total pancreatectomy should be
reserved to selected cases (non disease-free margins and PanIN-3).
This surgical technique presents high risk of morbidity and postoperative
complications such as uncontrolled diabetes which is the
leading cause of death.
Nevertheless, following surgical approach alone the median
overall survival (OS) range is 15-25 months. The adjuvant chemotherapy represents the current standard of care for pancreatic
adenocarcinomas in stage Ia-III which underwent R0-R1 surgery
and in selected cases is possible a subsequent treatment with
chemoradiation. Currently, the only evidence-based treatment is a
monochemotherapy with Gemcitabine IV or 5 Fluorouracil/folinic
acids IV, with an improvement of 10% at 5 years OS and a significant
reduction for recurrence risk [57-60]. Nowadays, many clinical
trials investigate the addition of Nab-Paclitaxel or Capecitabine
to Gemcitabine to improve the OS, but results are discordant [61].
Dedicated clinical trials results are still not available and the standard
of care of these patients remains controversial: in the routine practice
the regimens used in metastatic setting such as FOLFIRINOX
and Gemcitabine plus Nab-Paclitaxel are recommended [62].
First specific international trials are going to be designed as the
phase II as “LAPACT” with the combination of Gemcitabine plus
Nab-Paclitaxel [63,64]. Unresectable locally advanced disease or
metastatic disease represents 70% of all patients with pancreatic
cancer and require palliative treatments especially for symptoms
due to biliary obstruction with jaundice [65-67]. For these patients
the best palliation is represented by the placement of a biliary stent
endoscopically: a plastic stent in patients with limited life expectancy
and a short covered metal stent in patients with longer one. The plastic
stent could be placed even in those patients with borderline and
locally advanced disease in which it is expected down-staging after
neoadjuvant chemotherapy/chemoradiotherapy [68,69]. Regardless
of stage of disease, in patients with neoplastic duodenal stenosis with
subsequent digestive obstruction and obstructive jaundice it should
be considered derivative biliary-digestive surgery. Other possible
approaches to locally advanced pancreatic cancer are the use of
Radiofrequency Ablation (RFA) or Irreversible Electroporation (IRE).
These procedures are reported in literature to be safe and feasible
although there is a lack of randomized studies to corroborate these
findings. RFA is an ablative procedure consisting in high frequency
current applied to neoplastic tissue via one or more needle electrodes
that generates a local high temperature, causing coagulative necrosis
and protein denaturation. Instead, IRE is a non-thermal technique
that uses short high-voltage electric pulses conducted via monopolar
electrodes causing irreversible damage to cell membrane and thus
activating apoptotic pathways. The main advantage of this procedure
compared to RFA is the preservation of surrounding structures like
nerves or blood vessels [70].
Table 1
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