Transcript Pancreas CANCER - poursinahakim.ir

Pancreas CANCER
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Pancreas Exocrin Cancer
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Clinical manifestations, diagnosis, and staging of exocrine
pancreatic cancer
Pathology of exocrine pancreatic neoplasms
Epidemiology and risk factors for exocrine pancreatic cancer
Molecular pathogenesis of exocrine pancreatic cancer
Endoscopic ultrasound in the staging of exocrine pancreatic
cancer
Surgery in the treatment of exocrine pancreatic cancer and
prognosis
Adjuvant and neoadjuvant therapy for exocrine pancreatic
cancer
Chemotherapy for advanced exocrine pancreatic cancer
Management of locally advanced and borderline resectable
exocrine pancreatic cancer
Exocrine pancreatic cancer: Palliation of symptoms
Pancreas Exocrin Cancer
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Epidemiology and risk factors for exocrine pancreatic cancer
Molecular pathogenesis of exocrine pancreatic cancer
Endoscopic ultrasound in the staging of exocrine pancreatic
cancer
Surgery in the treatment of exocrine pancreatic cancer and
prognosis
Adjuvant and neoadjuvant therapy for exocrine pancreatic
cancer
Chemotherapy for advanced exocrine pancreatic cancer
Management of locally advanced and borderline resectable
exocrine pancreatic cancer
Exocrine pancreatic cancer: Palliation of symptoms
Pancreas Exocrin Cancer
Clinical manifestations, diagnosis, and staging of exocrine pancreatic cancer

The commonly used term "pancreatic cancer" usually refers
to a ductal adenocarcinoma of the pancreas (including its
subtypes).

More than 95 percent of malignant neoplasms of the pancreas
arise from the exocrine elements and are referred to as exocrine
pancreatic cancers. (See 'Pathology' above.)
Management of locally advanced and borderline resectable exocrine
pancreatic cancer
• cancer of the exocrine pancreas
• almost all are expected to die from the disease
• Surgical resection offers the only chance of cure
• Only 15 to 20 percent of patients have resectable disease
at diagnosis;
• approximately 40 percent have metastatic disease,
• and another 30 to 40 percent have locally advanced
unresectable tumors.
• Median survival is 8 to 12 months for patients with
locally advanced disease and less for those with
metastatic disease at presentation.
Pancreas Exocrin Cancer
Clinical manifestations, diagnosis, and staging of exocrine pancreatic cancer
The most common presenting symptoms in patients with
exocrine pancreatic cancer are
pain,
jaundice, and
weight loss.
Compared to tumors in the body and tail of the gland,
pancreatic head tumors more often present with jaundice,
steatorrhea, and weight loss.
Pancreas Exocrin Cancer
Clinical manifestations, diagnosis, and staging of exocrine pancreatic cancer
1.
Patients who present with jaundice or epigastric pain and
weight loss often undergo right upper quadrant
transabdominal ultrasound initially to evaluate for dilated
bile ducts or a pancreatic mass.
Pancreas Exocrin Cancer
Clinical manifestations, diagnosis, and staging of exocrine pancreatic cancer
In the jaundiced patient,
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ultrasound is highly sensitive for
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Endoscopic retrograde cholangiopancreatography (ERCP)
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detecting biliary tract dilation and
establishing the level of obstruction;
it is highly sensitive for pancreatic masses >3 cm.
is a highly sensitive tool for visualization of the biliary tree and pancreatic ducts
in patients with jaundice.
However, the role of ERCP in patients with suspected pancreatic cancer is
evolving into a mainly therapeutic rather than diagnostic modality in patients
who present with cholestasis due to tumor obstruction of the biliary system.
An alternative approach is magnetic resonance cholangiopancreatography
(MRCP).
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is generally reserved for patients with gastric outlet or duodenal stenosis,
or who have had surgical rearrangement (eg, Billroth II)
or ductal disruption, resulting in ducts that are difficult to assess successfully by
ERCP, in the setting of chronic pancreatitis,
or for patients in whom attempted ERCP is either totally unsuccessful or
provides incomplete information because of pancreatic duct obstruction. .
Pancreas Exocrin Cancer
Clinical manifestations, diagnosis, and staging of exocrine pancreatic cancer
For patients with epigastric pain and weight loss without
jaundice,
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in whom the differential diagnosis includes pancreatitis,
transabdominal ultrasound is not the preferred initial test
because it is associated with a high frequency of incomplete
examinations owing to overlying bowel gas due to ileus,
and it cannot clearly identify necrosis within the pancreas;
these important findings are best seen by contrast enhanced
CT scan.
Pancreas Exocrin Cancer
Clinical manifestations, diagnosis, and staging of exocrine pancreatic cancer
1.
Endoscopic ultrasound (EUS) may be of use in a patient
who is suspected of having pancreatic cancer based upon
the clinical presentation of jaundice, unexplained upper
abdominal pain/weight loss, or an unexplained episode of
pancreatitis, but who has no evidence of a mass lesion on
initial transabdominal ultrasound or CT.
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Given the limited sensitivity and specificity, the serum
tumor marker CA 19-9 should not be used as a diagnostic
test for pancreatic cancer.
Pancreas Exocrin Cancer
Clinical manifestations, diagnosis, and staging of exocrine pancreatic cancer
1.
Histologic confirmation is required to establish a diagnosis
of pancreatic cancer.
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Biopsy of a pancreatic mass can be accomplished through
percutaneous or endoscopic approaches.
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However, not all patients require a preoperative biopsy,
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and the next step in the workup of a patient with suspected
pancreatic cancer is often a staging evaluation to establish
disease extent and resectability rather than biopsy.
Pancreas Exocrin Cancer
Clinical manifestations, diagnosis, and staging of exocrine pancreatic cancer

When a mass lesion of the pancreas is detected on CT or
ultrasound,

it is reasonable to conclude that a neoplasm (most likely malignant) is
present, and triple-phase, contrast enhanced helical (preferably
multidetector row) CT is an appropriate next step to assess disease
extent and resectability.
 Local unresectability is usually (but not always) due to


vascular invasion, particularly of the superior mesenteric artery (SMA).
Endoscopic ultrasound (EUS) is another effective method to assess
tumor extent and vascular invasion,
 but we generally prefer CT given its greater utility in assessing for
distant metastases.
Pancreas Exocrin Cancer
Clinical manifestations, diagnosis, and staging of exocrine pancreatic cancer
o
Although practice is variable, most surgeons would consider a pancreatic
cancer to be categorically unresectable if any of the following are present:
o Extensive peripancreatic lymphatic involvement, nodal involvement
beyond the peripancreatic tissues, and/or distant metastases.
o
Direct involvement of the superior mesenteric artery (SMA), inferior vena
cava, aorta, celiac axis, or hepatic artery,
o
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o
as defined by the absence of a fat plane between the low density tumor and these
structures on CT scan.
Encasement (more than one-half of the vessel circumference)
or occlusion/thrombus of the superior mesenteric vein (SMV) or the SMV-portal
vein confluence used to be universally considered an indicator of unresectability.
However, many centers have demonstrated the feasibility of SMV
reconstruction, and this is now considered by many to represent borderline
resectable disease; in practice, most of these patients are referred for
neoadjuvant therapy prior to surgery.
Pancreas Exocrin Cancer
Clinical manifestations, diagnosis, and staging of exocrine pancreatic cancer
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The utility of PET scans, chest CT, and MRI in the
staging workup of suspected pancreatic cancer,
particularly whether any of these imaging studies
provides information beyond that obtained by
triple-phase, contrast enhanced helical multidetector
row CT remains uncertain, and we do not routinely
order these tests
Pancreas Exocrin Cancer
Clinical manifestations, diagnosis, and staging of exocrine pancreatic cancer

Assessment of serum levels of the tumor marker CA
19-9 prior to surgery and following resection, if
elevated, is valuable to assist in prognostication.

In addition, serial monitoring of CA 19-9 levels, if
initially elevated, is useful to follow patients after
potentially curative surgery and for those who are
receiving chemotherapy for advanced disease.
Pancreas Exocrin Cancer
Clinical manifestations, diagnosis, and staging of exocrine pancreatic cancer

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Our general diagnostic approach, as detailed in the following
sections, is summarized in the algorithm ( algorithm 2 ). In
general:
Tissue diagnosis is mandatory for patients who are
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unfit to undergo a major resection,
for those with a high suspicion of metastatic disease,
and for any patient being considered for neoadjuvant therapy
because of locally advanced nonmetastatic disease.
EUS-guided FNA is the best modality for obtaining a tissue
diagnosis, even if the tumor is poorly visualized by other
imaging modalities.
Pancreas Exocrin Cancer
Clinical manifestations, diagnosis, and staging of exocrine pancreatic cancer
3.
If a patient is a reasonable surgical candidate, and if the
clinical presentation and imaging are typical for a resectable
adenocarcinoma, it is reasonable to proceed to surgery
without a tissue diagnosis.
Pancreas Exocrin Cancer
Clinical manifestations, diagnosis, and staging of exocrine pancreatic cancer
4.
For jaundiced patients with no involvement or minimal
involvement of the major vessels and no evidence of distant
metastases on radiographic imaging,

we proceed directly to open laparotomy.
Pancreas Exocrin Cancer
Clinical manifestations, diagnosis, and staging of exocrine pancreatic cancer
For non-jaundiced patients (including all those
with body or tail tumors), as well as those with
major but incomplete involvement of the vascular
structures (eg, tumor contiguous to less than onehalf of the vessel circumference),
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we perform preoperative laparoscopy to exclude tiny
metastases that might have been overlooked by CT.
If the laparoscopy is negative, we then proceed to open
laparotomy to assess resectability.
Other indications for a staging laparoscopy prior to open
laparotomy include
 a high preoperative CA 19-9 level (>1000 units/mL)
 and any patient for whom high-quality imaging is in
any way suggestive of occult metastatic disease.
Pancreas Exocrin Cancer
Clinical manifestations, diagnosis, and staging of exocrine pancreatic cancer
Pancreas Exocrin Cancer
Clinical manifestations, diagnosis, and staging of exocrine pancreatic cancer
Pathology of exocrine pancreatic
neoplasms
Pancreas Exocrin Cancer
Pathology of exocrine pancreatic neoplasms
• The pancreas gives rise to several malignant and benign
neoplasms.
• The most common benign pancreatic neoplasm is serous
cystadenoma.
• Several neoplasms formerly classified as benign are now
accorded “premalignant” status because it is considered that
some will progress to malignancy.
• These include
• low-grade intraductal mucinous papillary neoplasm
(IPMN)
• mucinous cystic neoplasm (MCN).
Pancreas Exocrin Cancer
Pathology of exocrine pancreatic neoplasms
• A number of types of malignant tumors arise in the exocrine
pancreas.
• The commonly used term "carcinoma of the pancreas" or
"pancreatic cancer" usually refers to ductal
adenocarcinoma, which represents about 85 percent of
all pancreatic neoplasms.
• The more inclusive term "exocrine pancreatic neoplasms"
includes all tumors that are related to the pancreatic ductal
and acinar cells and their stem cells.
• More than 95 percent of malignant neoplasms of the
pancreas arise from the exocrine elements.
• The remainder arise from the endocrine elements within
the pancreas (the islet cells).
Pancreas Exocrin Cancer
Epidemiology and risk factors for exocrine pancreatic cancer
The major risk factors for pancreatic cancer are:
•Cigarette smoking .
•High body mass and lack of physical activity
•Nonhereditary chronic pancreatitis
•A role for familial aggregation and/or genetic factors is suggested by
the fact that 5 to 10 percent of patients with pancreatic cancer have a
first degree relative with the disease .
•Hereditary pancreatitis is an autosomal dominant disorder that
accounts for a small fraction of cases of chronic pancreatitis.
•The majority of affected individuals develop symptoms before the
age of 20 and often before the age of five .
•Germline mutations in known cancer-causing genes, such as BRCA1,
BRCA2, and STK11 (the gene mutated in Peutz-Jeghers syndrome) are
associated with an increased risk of pancreatic cancer
•Ataxia-telangiectasia is associated with an increased risk of pancreatic
cancer .
Pancreas Exocrin Cancer
Epidemiology and risk factors for exocrine pancreatic cancer
• The optimal timing and frequency of screening for
pancreatic cancer in individuals at elevated risk is
uncertain.
• Some expert groups recommend screening for high-risk
individuals who have a 5 or 10-fold or higher risk of
pancreatic cancer ( table 2 ) .
• The optimal time to begin screening is unclear, but some
groups recommend beginning at age 40 for those with
hereditary pancreatitis and 10 years before the age at which
pancreatic cancer was first diagnosed in individuals with an
inherited predisposition.
• In patients with PJS, screening for pancreatic cancer is
recommended at age 30 years.
• There is no consensus on the appropriate interval for
screening and also no consensus as to the optimal screening
strategy.
Pancreas Exocrin Cancer
Epidemiology and risk factors for exocrine pancreatic cancer
• Potential candidates for screening for pancreatic cancer
An affected individual with PJS
An affected individual with hereditary pancreatitis
Three or more first-, second-, or third-degree relatives with pancreatic cancer,
with ≥1 pancreatic cancer in a first-degree relative*
A known mutation carrier of a BRCA1 , • BRCA2 , p16 , MLH1 , • MSH2 , •
MSH6 , • or PMS2 • mutation and ≥1 first- or second- degree relative with
pancreatic cancer
Pancreas Exocrin Cancer
Adjuvant and neoadjuvant therapy for exocrine pancreatic cancer
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Cancer of the exocrine pancreas is associated with a poor
prognosis, even if a complete (R0) resection can be
accomplished.
Systemic chemotherapy, radiation therapy (RT), and a
combination of chemotherapy and RT have all been applied
following surgery in an effort to improve cure rates.
Although the benefit of adjuvant therapy has become
clearer in recent years, the optimal choice of treatment
modality (chemotherapy with or without RT) remains
intensely controversial.
Pancreas Exocrin Cancer
Adjuvant and neoadjuvant therapy for exocrine pancreatic cancer

There is no consensus regarding the optimal management of
patients after resection of an exocrine pancreatic cancer, and
the approach is different in Europe and in the United States:
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Largely based upon
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most European clinicians use chemotherapy alone after
resection of a pancreatic neoplasm.
Where available, oral therapy with S-1 represents an
appropriate alternative to gemcitabine monotherapy.
The American approach more often includes
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the ESPAC-1 trial, which showed that 5-FU-containing
chemotherapy prolongs survival,
and results of the German CONKO trial showing a survival benefit
from adjuvant gemcitabine
chemoradiotherapy as well as adjuvant chemotherapy.
Guidelines from the NCCN support either approach.
Pancreas Exocrin Cancer
Adjuvant and neoadjuvant therapy for exocrine pancreatic cancer
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The following represents approach to patients with resected
pancreatic tumors.
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Eligible patients should be encouraged to enroll in clinical trials
evaluating the potential benefits of chemotherapy and/or
chemoradiotherapy as well as new therapies.
Continue
Pancreas Exocrin Cancer
Adjuvant and neoadjuvant therapy for exocrine pancreatic cancer
1.
The following represents approach to patients with resected
pancreatic tumors.
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Off-protocol, we suggest a combination of concurrent
chemoradiotherapy and chemotherapy for all patients with resected
pancreatic cancer ( Grade 2B ).
During the concurrent chemoradiotherapy portion, we prefer infusional
5-FU, and we use gemcitabine alone for the chemotherapy portion.
Continue
Pancreas Exocrin Cancer
Adjuvant and neoadjuvant therapy for exocrine pancreatic cancer
1.
The following represents approach to patients with resected
pancreatic tumors.
1.
The optimal way to sequence 5-FU-based chemoradiotherapy and
gemcitabine chemotherapy is unclear. An acceptable regimen is that
used in RTOG 9704 [ 38 ], which consists of
three weekly doses of gemcitabine alone (1000 mg/m 2 per week),
followed by chemoradiotherapy using concurrent infusional 5-FU.
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Although the RTOG trial used 250 mg/m 2 daily continuously, many
clinicians, including our group, consider this too toxic and use 225 mg/m 2
daily, five days per week.
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Following chemoradiotherapy and starting three to five weeks later, three
months of single agent gemcitabine ( table 2 ) are given. (See 'Gemcitabinebased approaches' above and "Treatment protocols for pancreatic cancer" .)
Pancreas Exocrin Cancer
Adjuvant and neoadjuvant therapy for exocrine pancreatic cancer
1.
Although neoadjuvant chemoradiotherapy can be safely
delivered to patients with localized pancreatic cancer, no
study has clearly demonstrated improved resectability or
survival, and it remains unclear whether this approach
provides comparable benefit to adjuvant (postoperative)
therapy.
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We suggest not administering neoadjuvant
chemoradiotherapy outside of clinical trials at present
(Grade2C ).
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Eligible patients should be encouraged to enroll on clinical trials
testing this strategy. (See'Neoadjuvant therapy for potentially
resectable tumors' above.)
Pancreas Exocrin Cancer
Adjuvant and neoadjuvant therapy for exocrine pancreatic cancer
1.
GITSG study
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observation or
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external beam RT (EBRT, 40 Gy) plus concurrent bolus 5FU (500 mg/m 2 per day on the first three and last three
days of RT),
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followed by maintenance chemotherapy (5-FU 500 mg/m 2
per day for three days monthly) for two years or until
disease progression
patients receiving postoperative chemoradiotherapy had
significantly longer median overall survival (20 versus 11
months) and a doubling of the two-year survival rate (20 versus
10 percent)
Pancreas Exocrin Cancer
Adjuvant and neoadjuvant therapy for exocrine pancreatic cancer
2.
EORTC study
postoperative concurrent 5-FU (25 mg/kg per day by continuous infusion)
plus EBRT (40 Gy in split courses)
or observation
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2.
1.
In contrast to the GITSG findings, postoperative chemoradiotherapy did not
significantly improve median overall survival or two-year survival (26 versus 34
percent for control and treated patients, respectively, p = 0.099
Pancreas Exocrin Cancer
Adjuvant and neoadjuvant therapy for exocrine pancreatic cancer
ESPAC-1 trial
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2x2 factorial design in which the relative benefits of
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adjuvant chemotherapy,
chemoradiotherapy, or
chemoradiotherapy followed by chemotherapy
observation alone
chemoradiotherapy consisted of 20 Gy EBRT plus three days of concomitant 5-FU,
repeated after a planned break of two weeks.
adjuvant chemotherapy consisted of bolus leucovorin -modulated 5-FU (leucovorin 20
mg/m 2 , 5-FU 425 mg/m 2 ), administered daily for five days, every 28 days, for six months.
Pancreas Exocrin Cancer
Adjuvant and neoadjuvant therapy for exocrine pancreatic cancer
2.
ESPAC-1 trial
Pancreas Exocrin Cancer
Adjuvant and neoadjuvant therapy for exocrine pancreatic cancer
2.
ESPAC-1 trial
Pancreas Exocrin Cancer
Adjuvant and neoadjuvant therapy for exocrine pancreatic cancer
2.
ESPAC-1 trial
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This analysis was criticized for the following reasons:
Patients and clinicians were allowed to select which trial to enter, raising
concerns as to generalizability and the appropriateness of combining results.
Clinicians were allowed, according to their own preferences, to deliver
"background" chemoradiation or chemotherapy.
Comparisons of treatment groups that were pooled together by treatment
actually received, rather than "intent-to-treat" analysis, resulted in nearly onethird of the "no chemotherapy" and "chemotherapy alone" patients receiving
chemoradiotherapy.
Similar to the EORTC trial discussed above, the chemoradiotherapy group
received RT in a split course fashion, and the final dose (ranging from 40 to 60
Gy) was left to the judgment of the treating physician.
The chemoradiotherapy group did not include postradiotherapy adjuvant
chemotherapy; thus, the results cannot be directly compared to the results of
the GITSG trial.
Pancreas Exocrin Cancer
Adjuvant and neoadjuvant therapy for exocrine pancreatic cancer
Chemotherapy only
 Gemcitabine
 CONKO trial
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368 patients with grossly complete (R0 or R1) surgical resection and a
preoperative CA 19-9 level <2.5 times the upper limit of normal

gemcitabine (1000 mg/m 2 days 1, 8, and 15 every four weeks for
six months) or no treatment after surgery
significantly longer median DFS (13.4 versus 6.9 months),
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which was evident in those with
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negative nodes (24.8 versus 10.4 months) and
positive (12.1 versus 6.4 months),
as well as those with negative margins (13.1 versus 7.3 months) or
positive (15.8 versus 5.5 months).
ASCO meeting, there was also a modest but significant
improvement overall survival that favored gemcitabine (median
22.8 versus 20.2 months, p = 0.005, five-year survival 21 versus 9
percent)
Pancreas Exocrin Cancer
Adjuvant and neoadjuvant therapy for exocrine pancreatic cancer
Chemotherapy only
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Gemcitabine versus a fluoropyrimidine
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ESPAC-3 trial
1088 patients with resected exocrine pancreatic cancer to
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six months of postoperative adjuvant treatment with either gemcitabine
(1000 mg/m 2 weekly for three of every four weeks) or
leucovorin modulated 5-FU (leucovorin 20 mg/m 2 followed by 5-FU 425
mg/m 2 IV bolus days 1 through 5, every 28 days) [ 46 ]
At a median follow-up of 34 months, median survival was similar (23.6
versus 23 months with gemcitabine and fluoropyrimidine therapy,
respectively).
the patients assigned to 5-FU/leucovorin had more grade 3 to 4 treatmentrelated toxicity
Given this safety profile, gemcitabine is the preferred agent when
compared with monthly bolus (Mayo Clinic) 5-FU/LV.
Pancreas Exocrin Cancer
Adjuvant and neoadjuvant therapy for exocrine pancreatic cancer
Chemotherapy only
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Gemcitabine versus a fluoropyrimidine
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ESPAC-3 trial
1088 patients with resected exocrine pancreatic cancer to
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six months of postoperative adjuvant treatment with either gemcitabine
(1000 mg/m 2 weekly for three of every four weeks) or
leucovorin modulated 5-FU (leucovorin 20 mg/m 2 followed by 5-FU 425
mg/m 2 IV bolus days 1 through 5, every 28 days) [ 46 ]
At a median follow-up of 34 months, median survival was similar (23.6
versus 23 months with gemcitabine and fluoropyrimidine therapy,
respectively).
the patients assigned to 5-FU/leucovorin had more grade 3 to 4 treatmentrelated toxicity
Given this safety profile, gemcitabine is the preferred agent when
compared with monthly bolus (Mayo Clinic) 5-FU/LV.
Pancreas Exocrin Cancer
Adjuvant and neoadjuvant therapy for exocrine pancreatic cancer
Chemotherapy only
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Gemcitabine versus a fluoropyrimidine
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Gemcitabine versus S-1
three different agents: ftorafur, chlorohydroxy dihydropyridine (a potent
inhibitor of DPD [dihydropyrimidine dehydrogenase])
S-1 (40 to 60 mg twice daily for four weeks and repeated every six weeks for
four courses)
In a preliminary report presented at the 2013 ASCO Gastrointestinal Cancers
Symposium, S-1 was not inferior to gemcitabine
S-1 represents a reasonable and more convenient alternative to gemcitabine
when adjuvant chemotherapy alone is recommended following resection of a
pancreatic cancer.
Pancreas Exocrin Cancer
Adjuvant and neoadjuvant therapy for exocrine pancreatic cancer
Chemotherapy versus chemoradiotherapy
Two good design Trail
 ESPAC-1 trial,
 EORTC 40013/FFCD-9203/GERCOR phase II study



Ninety patients with resected pancreatic cancer (70 percent node-positive, 97 percent
completely resected [R0]) were randomly assigned to gemcitabine -based
chemoradiotherapy (two cycles of weekly gemcitabine alone [1000 mg/m 2 weekly, three
weeks on, one week off]) followed by RT (50.4 Gy in 28 daily 1.8 Gy fractions) with
concurrent gemcitabine (300 mg/m 2 once weekly four hours before RT for five to six
weeks), or a control group.
Initially the control group was observation alone (n = 4), but the protocol was amended,
and the remainder of the control group (n = 41) received four cycles of gemcitabine
alone (1000 mg/m 2 for three consecutive weeks followed by a one week rest). Treatment
started within eight weeks of surgery.
chemoradiotherapy was not deleterious; median DFS was 12 versus 11 months in the
control group, and median overall survival was 24 months in both arms.
Pancreas Exocrin Cancer
Adjuvant and neoadjuvant therapy for exocrine pancreatic cancer
Chemotherapy versus chemoradiotherapy
Two good design Trail
 ESPAC-1 trial,
 EORTC 40013/FFCD-9203/GERCOR phase II study



Ninety patients with resected pancreatic cancer (70 percent node-positive, 97 percent
completely resected [R0]) were randomly assigned to gemcitabine -based
chemoradiotherapy (two cycles of weekly gemcitabine alone [1000 mg/m 2 weekly, three
weeks on, one week off]) followed by RT (50.4 Gy in 28 daily 1.8 Gy fractions) with
concurrent gemcitabine (300 mg/m 2 once weekly four hours before RT for five to six
weeks), or a control group.
Initially the control group was observation alone (n = 4), but the protocol was amended,
and the remainder of the control group (n = 41) received four cycles of gemcitabine
alone (1000 mg/m 2 for three consecutive weeks followed by a one week rest). Treatment
started within eight weeks of surgery.
chemoradiotherapy was not deleterious; median DFS was 12 versus 11 months in the
control group, and median overall survival was 24 months in both arms.
Pancreas Exocrin Cancer
Adjuvant and neoadjuvant therapy for exocrine pancreatic cancer
Radiation therapy alone
 Few data address the benefit of adjuvant EBRT alone after
potentially curative surgery
 intraoperative RT (IORT) in conjunction with surgical
resection???
 Most trials have combined IORT with preoperative EBRT and
chemotherapy (see below); none are randomized with a
control group of resection without IORT.
Pancreas Exocrin Cancer
Adjuvant and neoadjuvant therapy for exocrine pancreatic cancer

Summery for adj CCR
Pancreas Exocrin Cancer
Adjuvant and neoadjuvant therapy for exocrine pancreatic cancer

There is no consensus regarding the optimal management of
patients following resection of pancreatic cancer, and the
approach is different in Europe and in the United States.
Pancreas Exocrin Cancer
Adjuvant and neoadjuvant therapy for exocrine pancreatic cancer

The European approach
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
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emphasizes the weaknesses of the early GITSG study and the
lack of data demonstrating a significant survival benefit with
chemoradiotherapy in the EORTC and ESPAC-1 trials.
Most European clinicians support the conclusions of the
ESPAC-1 trial (ie, that chemotherapy prolongs survival and
chemoradiotherapy may actually worsen survival).
The benefit of adjuvant chemotherapy alone is further
supported by the German CONKO trial [ 40 ].
Guidelines for treatment of pancreatic adenocarcinoma from the
European Society of Medical Oncology suggest that
chemoradiotherapy in the adjuvant setting should only be
performed within the context of a randomized controlled trial [
56 ]
Pancreas Exocrin Cancer
Adjuvant and neoadjuvant therapy for exocrine pancreatic cancer

The American approach to adjuvant therapy differs with
regard to the benefit of chemoradiotherapy and emphasizes
the following points:
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


The high risk of local failure and potential for benefit from
chemoradiotherapy
The high rate of positive retroperitoneal margins and the impact
of this finding on survival
The survival benefit from chemoradiotherapy in the GITSG
study
The trend toward improved survival seen with
chemoradiotherapy in the underpowered EORTC study
The serious design flaws of the ESPAC-1 trial and the inherent
difficulty in drawing definitive conclusions from this study
Pancreas Exocrin Cancer
Adjuvant and neoadjuvant therapy for exocrine pancreatic cancer

In the opinion of the uptodate and NCCN ,

patients who have undergone resection of an exocrine
pancreatic cancer should be encouraged to enroll in clinical
trials evaluating the potential benefits of chemotherapy and/or
chemoradiotherapy as well as new therapies.

As an example, RTOG trial 0848 is a phase III trial examining
the benefit of adding erlotinib to adjuvant gemcitabine with or
without subsequent fluoropyrimidine-based
chemoradiotherapy in patients with resected tumors of the head
of the pancreas [ 57 ].
Pancreas Exocrin Cancer
Adjuvant and neoadjuvant therapy for exocrine pancreatic cancer

Off protocol, NCCN guidelines suggest 5-FU-based
chemoradiotherapy plus systemic gemcitabine or
chemotherapy alone (5-FU or gemcitabine).

Given the results of the European ESPAC-3 trial [ 58 ], the
NCCN panel suggests gemcitabine rather than leucovorin modulated 5-FU during the adjuvant chemotherapy
component of therapy following resection of an exocrine
pancreatic cancer.

The early results from RTOG 9704 combined with the results
from the CONKO trial provide support for adding
gemcitabine adjuvant chemotherapy to chemoradiotherapy,
at least for patients with pancreatic head tumors. The benefit
of this approach is unproven for body/tail lesions, but we
tend to treat these patients similarly.
Pancreas Exocrin Cancer
Adjuvant and neoadjuvant therapy for exocrine pancreatic cancer

The optimal way to sequence 5-FU-based chemoradiotherapy and
gemcitabine alone is unclear.

An acceptable regimen is that used in RTOG 9704, which consists
of three weekly doses of gemcitabine alone (1000 mg/m 2 per
week), followed by chemoradiotherapy with concurrent infusional
5-FU [ 38 ].

Although the RTOG trial used 5-FU 250 mg/m 2 daily, many
clinicians find this dose excessively toxic and instead use 225 mg/m
2 daily, five days per week.

Following chemoradiation and starting three to five weeks later,
patients receive three months of single agent gemcitabine

However, based upon logistical concerns as well as postoperative
morbidity, clinicians may sequence chemoradiotherapy and
gemcitabine differently than in the RTOG study.
Pancreas Exocrin Cancer
Adjuvant and neoadjuvant therapy for exocrine pancreatic cancer
NEOADJUVANT THERAPY FOR POTENTIALLY RESECTABLE TUMORS

The rationale for neoadjuvant approaches includes:




Improve the selection of patients for whom resection will not offer a survival
benefit (ie, those who rapidly progress to metastatic disease during
preoperative therapy)
Increase rates of margin-negative resections
Early treatment of micrometastatic disease
5 FU-based therapy

initial reports of preoperative radiation therapy (RT) with or
without concurrent 5-FU
 demonstrated that this approach did not worsen perioperative
morbidity and mortality,
 there was no obvious improvement in either resectability or
overall survival
Pancreas Exocrin Cancer
Adjuvant and neoadjuvant therapy for exocrine pancreatic cancer
NEOADJUVANT THERAPY FOR POTENTIALLY RESECTABLE TUMORS

Gemcitabine-based chemoradiotherapy



Median survival for the entire group was 17.4 months;
it was 31 versus 10.5 months for the patients who did versus did not undergo
pancreaticoduodenectomy, respectively.
Meta-analyses



A meta-analysis of 14 phase II trials concluded that among patients with
potentially resectable pancreatic cancer, the rate of potentially curative
resection after neoadjuvant therapy was 66 percent and median survival in the
resected patients was 23 months [ 78 ].
A second meta-analysis of seven prospective but uncontrolled trials of
gemcitabine -based neoadjuvant therapy in this setting concluded that 89
percent of initially resectable patients were able to undergo potentially curative
resection, with a median survival in the resected patients of 31 months [ 79 ].
A third analysis of 111 studies, including 56 phase I/II trials, with 96 percent of
the patients receiving chemotherapy and 94 percent RT, concluded that among
patients with initially resectable disease, 35 percent had an objective response
to neoadjuvant therapy while 21 percent had progressive disease [ 80 ].
Resectability rates were 74 percent.
Pancreas Exocrin Cancer
Adjuvant and neoadjuvant therapy for exocrine pancreatic cancer
NEOADJUVANT THERAPY FOR POTENTIALLY RESECTABLE TUMORS

However, whether these results represent an improvement
in outcomes in patients who undergo resection without
neoadjuvant therapy is unclear, given the lack of a surgery
alone control arm in any of the trials included in any of the
analyses. Thus, at present this cannot be considered a
standard approach.
Pancreas Exocrin Cancer
Adjuvant and neoadjuvant therapy for exocrine pancreatic cancer
NEOADJUVANT THERAPY FOR POTENTIALLY RESECTABLE TUMORS

Neoadjuvant chemoradiotherapy




can be safely delivered to patients with localized pancreatic
cancer without adversely influencing perioperative
morbidity or mortality.
However, no study has clearly demonstrated improved
resectability or survival compared to patients treated with
surgery alone,
and it remains unclear whether this approach provides
benefit compared to adjuvant (postoperative) therapy.
The first US national trial of neoadjuvant therapy for
potentially resectable pancreatic cancer (ACOSOG Z5041) is
open, and eligible patients should be encouraged to enroll
Pancreas Exocrin Cancer
Adjuvant and neoadjuvant therapy for exocrine pancreatic cancer
POSTTREATMENT SURVEILLANCE
 There is no evidence to guide the posttreatment surveillance



detect local or distant recurrence
most recurrences are not amenable to potentially curative therapy
early introduction of palliative chemotherapy or radiation therapy

American Society of Clinical Oncology does not provide formal
recommendations

National Comprehensive Cancer Network (NCCN) recommend a history
and physical examination for symptom assessment every three to six
months for two years, then annually with low level of evidence but
uniform consensus.
They suggest the use of CA 19-9 determinations and follow-up CT scans
every three to six months for two years after surgical resection, then
annually on the basis of low level evidence with nonuniform consensus.

Management of locally advanced and borderline resectable exocrine pancreatic cancer

Consensus-based guidelines from the National Comprehensive Cancer Network
define the following characteristics as indicating unresectability

Head of pancreas lesions




Body




SMA or celiac encasement greater than 180 degrees
Unreconstructable SMV/portal vein occlusion
Aortic invasion
Tail


Greater than 180 degrees SMA encasement, any celiac abutment
Unreconstructable SMV/portal vein occlusion
Aortic invasion or encasement
SMA or celiac encasement greater than 180 degrees
For all sites


Distant metastases
Metastases to lymph nodes beyond the field of resection
Management of locally advanced and borderline resectable exocrine pancreatic cancer

Locally advanced, unresectable
 Approximately
40 percent of patients with
pancreatic cancer present with locally advanced,
unresectable nonmetastatic disease, typically a T4
lesion .
 The optimal management of these patients is
controversial.
 Therapeutic options include
radiation therapy (RT) alone,
 chemoradiotherapy, and
 chemotherapy alone.

Management of locally advanced and borderline resectable exocrine pancreatic cancer

Locally advanced, unresectable

For most patients, we suggest an initial period of chemotherapy
rather than chemoradiotherapy(Grade 2C ).

This approach has the advantage of sparing those patients who
have rapidly progressive disease in the liver or peritoneum from
undergoing RT.)

Gemcitabine monotherapy represents a standard approach. For
patients with an excellent performance status, and a total bilirubin
level that is below 1.5 times the upper limit of normal,
combination chemotherapy with FOLFIRINOX ( table 2 ) is an
option.



However, clinicians should be cautioned that until prospective
trials and larger retrospective experiences with FOLFIRINOX in
this setting are published,
toxicity remains an extremely important consideration and largely
unknown although it is assumed to be the same as in the metastatic
setting.
Management of locally advanced and borderline resectable exocrine pancreatic cancer

Locally advanced, unresectable
 For
patients who do not progress,
suggest combined treatment with external beam RT
(EBRT) plus concomitant low-dose infusional 5-FU (eg,
200 mg/m 2 daily) rather than RT alone ( Grade 2B ).
 suggest the substitution of capecitabine (or, where
available, S-1) for infusional 5-FU in patients for whom
ambulatory infusional therapy using a pump is not
considered feasible ( Grade 2B ).

Management of locally advanced and borderline resectable exocrine pancreatic cancer

Locally advanced, unresectable
 While
it is reasonable to restage and reevaluate
the potential for resectability after
chemoradiotherapy,
 the
frequency of a complete resection and longterm survival is low for patients who initially have
categorically unresectable tumors.
Management of locally advanced and borderline resectable exocrine pancreatic cancer

Borderline resectable
Some cases are considered "borderline" resectable, mostly
based upon vascular involvement, although the definition
is variable.
 Although some of these patients will prove to be resectable
with initial surgery, the likelihood of an incomplete
resection is high.
 An initial attempt at downstaging with chemotherapy,
chemoradiotherapy, or a combination followed by
restaging and surgical exploration in responders is a
reasonable approach for fit patients who are willing to
accept the uncertainty of clinical benefit from this
approach.
 The best form of induction therapy to use in this setting is
unclear. Whenever possible, such patients should be
encouraged to enroll on clinical trials testing new
approaches.

Exocrine pancreatic cancer: Palliation of symptoms
• Palliative treatment designed to control
• the symptoms of unresectable
• or recurrent pancreatic cancer
• can provide relief of
• obstructive jaundice,
• gastric outlet obstruction,
• pain and
• pancreatic exocrine insufficiency.
Exocrine pancreatic cancer: Palliation of symptoms
• Palliation of jaundice in patients with pancreatic cancer who
are not undergoing an attempt at surgical resection is
usually accomplished by the placement of an expandable
metal stent.
• Surgery is reserved for those in whom stent placement is not
possible due to technical reasons
• Endoscopically placed expandable metal stents are also
preferred over palliative gastrojejunostomy for patients with
symptomatic gastric outlet obstruction.
• Pain can be a significant feature of advanced pancreatic
cancer. (See 'Pain' above.)
• Often, palliation of pain can be successfully achieved by
opioid analgesics alone.
Exocrine pancreatic cancer: Palliation of symptoms
• Celiac plexus neurolysis appears to be more effective than
pharmacologic therapy both for immediate and long-term
relief of pain in patients with pancreatic cancer, and it can be
performed percutaneously or during endoscopic
ultrasound.
• Radiation therapy may also significantly alleviate pain due
to local invasion of pancreatic cancer; however, it may take
several weeks to see the maximal effect.
Exocrine pancreatic cancer: Palliation of symptoms
• Weight loss and cachexia in patients with pancreatic cancer
are usually multifactorial.
• One contributory factor may be pancreatic exocrine
insufficiency, which leads to fat malabsorption.
• Patients who are suspected of having fat malabsorption
should be treated with pancreatic enzyme replacement.