2. Anatomy
The pancreas is an elongated, coarsely lobulated
gland lying transversely and retroperitoneally in the
posterior abdomen
at approximately the L1 to L2 level
8. Epidemiology
Pancreatic cancer is the fifth leading cause of cancer
mortality among men and women of all ages
a male-to-female ratio of 1.3 : 1.
Diagnosis is rare before age 45 but rises sharply
thereafter
9. Causal Factors
Smoking -raises the relative risk 1.5 times.
Alcohol
Diets high in meat or fat also have been linked to
increased risk
a diet of fresh fruits and vegetables has been found to be
protective.
An increased incidence also is found with a prior history
of surgery for peptic ulcer disease
10. chronic pancreatitisare associated with
pancreatic cancer
One study showing 7 times higher risk
Long-term diabetes appears to be a risk
factor for pancreatic cancer
Chemical agents
Workers employed in manufacturing 2-
naphthylamine, benzidine,and gasoline are
reported to have a fivefold increased risk
11.
12. Genetics, and Cytogenetic Abnormalities
Pancreatic cancer is thought to have a familial
component in approximately 10% of cases
There are four specific genes identified as crucial in
the development of pancreatic cancer:
p16, p53, DPC4, and BRCA2
An example is the k-ras oncogene, which is often
activated in human pancreatic duct carcinomas.
13. 95% of pancreatic adenocarcinomas contain k-ras
oncogenes activated by a mutation at codon 12.
14.
15.
16. Germline mutations in the STK11 gene result in
Peutz-Jeghers syndrome
individuals have gastrointestinal polyps and a highly
elevated risk for colorectal cancers
highly elevated risk for developing pancreatic cancer,
reported to be increased by as much as 132-fold
17. Familial Malignant Melanoma syndrome (also
known as Melanoma-Pancreatic Cancer syndrome or
Familial Atypical Multiple Mole Melanoma
syndrome [FAMMM])
caused by germline mutation of the CDKN2A
(p16INK4a/p14ARF) gene.
This syndrome is associated with a 20-fold to 47-
fold increased risk for pancreatic cancer
18. Lynch syndrome also have an estimated 9- to 11-fold
elevated risk for pancreatic cancer
BRCA 1 N 2
The risk of pancreatic cancer is elevated 2- to 6-fold
in these patients
age of onset is younger than average
19. As many as 80% of patients with a family history of
pancreatic cancer have no known genetic cause.
having just 1 first-degree relative with pancreatic
cancer raises the risk of pancreatic cancer by 4.6 fold
having 2 affected first-degree relatives raises risk by
about 6.4-fold
20. Pancreatic Cancer Screening
high-risk individuals
defined as first-degree relatives of patients with
pancreatic cancer from familial kindreds;
carriers of p16 or BRCA2 mutations with an affected
first-degree relative
patients with Peutz-Jeghers syndrome
patients with Lynch syndrome and an affected first-
degree relative with pancreatic cancer.
21. Pathologic Conditions
The most common type of pancreatic cancer is of
ductal origin, comprising from 75% to 90% of
patients
It is twice as common in the head as in the body or
tail
Less frequently occurring exocrine tumors, such as
cystadenocarcinoma or intraductal carcinoma, are
more common in women
22. Solid and cystic papillary neoplasms, also
known as Hamoudi tumors, occur in women
in their third decade of life
rarely metastasize, and have a good
prognosis
Rare acinar cell cancers are associated with
fat necrosis and high lipase production and
have a poor prognosis
may be associated with a clinical picture that
includes rash, eosinophilia, and
polyarthralgia
23. Giant cell tumors, which account for only a
small percentage of pancreatic cancers, are
very large and aggressive and have a very
poor survival rate
metastases in the pancreas with the most
frequent primary sites being breast, lung, or
melanoma
5% of pancreatic cancers are of endocrine
origin
24. Location
66% in Head and Uncinate Process
Dx earlier ,
Symptomatic
15% in Body
10% in Tail
Usually larger & more progress at time of Dx
Asymptomaic
Other diffuse involvement
25. Clinical Presentation
More than 80% of patients present with pain,
jaundice, or both and weight loss
Infrequently, patients may present with migratory
thrombophlebitis (Trousseau sign)
or with a palpable gallbladder (Courvoisier sign).
29. The most commonly used diagnostic and staging
examination is an abdominal CT scan
Over 90% of patients deemed unresectable by CT are
actually unresectable at operation
CT can be utilized to facilitate fine-needle aspiration.
30.
31. EUS
In this procedure, an endoscope with an ultrasound
transducer at its tip is passed into the stomach and
duodenum
it provides high-resolution images of the pancreas and
surrounding vessels and facilitates needle biopsies
EUS is usually performed in conjunction with endoscopic
retrograde cholangiopancreatography (ERCP)
This combined diagnostic approach allows for staging,
therapeutic stenting of the common bile duct when
indicated, and retrieval of tumor cells by fine-needle
aspiration
32. (MRI) including high-resolution imaging, fast
imaging, volume acquisitions, functional imaging,
and MR cholangiopancreatograph
have led to an improved ability of MRI to diagnose
and stage pancreatic cancer
Used in patients with poor renal function
Small foci of hepatic mets are better detected by MRI
33. PET
Initial studies showed (PET) has a higher sensitivity,
specificity, and accuracy than CT in diagnosing
pancreatic carcinomas
more accurate than CT in identifying malignant
pancreatic cystic lesions
34. STAGING LAPROSCOPY
current imaging techniques cannot visualize small (1
to 2 mm) liver and peritoneal implants
staging laparoscopy has been used preoperatively to
exclude intraperitoneal metastases
can detect intraperitoneal metastases in up to 37% of
patients with apparently locally advanced disease by
CT
35. WHEN?
borderline resectable disease
markedly elevated CA 19-9
large primary tumors
large regional lymph nodes
highly symptomatic
36. Biopsy
Although a pathologic diagnosis is not required
before surgery
it is necessary before administration of neoadjuvant
therapy and for patients staged with locally
advanced, unresectable pancreatic cancer or
metastatic disease
often made using fine-needle aspiration (FNA)
biopsy with either EUS guidance (preferred) or CT
37. Pancreatic ductal brushings or biopsies can also be
obtained at the time of ERCP
42. CRITERIA DEFINING RESECTABILITY
STATUS
Resctable tumors
No distant metastases
No radiographic evidence of superior mesenteric
vein (SMV) or portal vein (PV) distortion.
Clear fat planes around the celiac axis, hepatic
artery, and SMA
43. borderline resectable
No distant metastases
Venous involvement of the SMV or PV with distortion or
narrowing of the vein or occlusion of the vein with
suitable vessel proximal and distal, allowing for safe
resection and replacement.
Gastroduodenal artery encasement up to the hepatic
artery with either short segment encasement or direct
abutment of the hepatic artery without extension to the
celiac axis.
Tumor abutment of the SMA not to exceed greater than
180 degrees of the circumference of the vessel wall
46. Surgical resection is the only potentially curative
technique for managing pancreatic cancer
more than 80% of patients present with disease that
cannot be cured with surgical resection
47. The goals of surgical extirpation of pancreatic
carcinoma focus on the achievement of an R0
resection
a margin positive specimen is associated with poor
long-term survival
Achievement of a margin negative dissection must
focus on meticulous perivascular dissection of the
lesion in resectional procedures, recognition of the
need for vascular resection and/or reconstruction
48. prognostic indicators for long-term patient survival
Negative margin status (ie, R0 resection)
Tumor DNA content
tumor size
absence of lymph node metastases
49. When deciding whether a patient is a surgical
candidate.
Age of the patient
Comorbidities
performance status
frailty are all things to be discussed
50. Primary Surgery for Pancreatic Cancer
The nature and extent of the surgery for resectable
tumors depend on the location and size of the tumor.
Because tumors of the body and tail cause symptoms
late in their development
they are usually advanced at diagnosis and are rarely
resectable.
51. Surgical Procedures
Tumors of the Body
and Tail
Distal Pancreatectomy
Removal of body & tail of
pancreas
spleen
52. Surgical Procedures
Head of the
pancreas: Whipple
Procedure
Removal of:
Distal stomach
Duodenum and
proximal jejunem
Head of pancreas
Gallbladder and
common bile duct
55. Total pancreatectomy
If the cancer diffusely involves the pancreas
or is present at multiple sites within the pancreas
where the surgeon removes
Entire pancreas, part of the small intestine, a portion
of the stomach, the common bile duct, the
gallbladder, the spleen, and nearby lymph nodes
56. If the tumor is found to be unresectable during
surgery
biopsy confirmation of adenocarcinoma can be done.
If a patient with jaundice is found to be unresectable
at surgery stenting or biliary bypass can be done
57. Lymph node dissection
A standard lymphadenectomy in patients undergoing
pancreatoduodenectomy
entails removal of nodes at the duodenum and pancreas
on the right side of the hepatoduodenal ligament, the
right side of the SMA
the anterior and posterior pancreatoduodenal lymph
nodes
58. Preoperative Biliary Drainage
The main goals of preoperative biliary drainage are
to alleviate the symptoms of pruritus and cholangitis
and to potentially make surgery less morbid by
improving liver function preoperatively.
But earlier study does not support use of
preoperative drainage routinely
59. It is considered
When surgery is delayed due to sepsis
When planned for neoadjuvant therapy
60. ADJUVANT THERAPY
Even with R0 resections, recurrence rates are very
high in this disease.
Additional therapy is required for all patients with
resected pancreatic adenocarcinoma.
61. PATTERN OF FAILURE
the bed of the resected pancreas (local recurrence)
the peritoneal cavity
liver
62. High local failure rates of 50% to 86% occur despite
resection
because of frequent cancer invasion into the
retroperitoneal soft tissues
high rates of lymphatic involvement
the inability to achieve wide retroperitoneal soft-
tissue margins because of anatomic constraints to
wide posterior excision
63. EARLIER STUDIES
GITSG trial, which enrolled patients with completely
resected pancreatic cancer
A total of 46 patients were randomized to undergo
observation
or to receive bolus 5-FU (500 mg/m2 daily) during
the first 3 days of each period of split course
radiation
20 Gy in 10 fractions, 2 weeks break, and
resumption of radiation to a total dose of 40 Gy
64. followed by up to 2 years of weekly bolus 5-FU
striking survival advantage for patients receiving
combined modality therapy compared with survival
of patients who underwent surgery alone
median 21.0 months vs. 10.9 months, respectively; P
= .03
65. The findings from the GITSG study could not be
reproduced by a subsequent trial conducted by the
EORTC
EORTC-40891 randomized 218 patients
undergo observation or to receive infusional 5-FU
(25 mg/kg/d to a maximum dose of 1,500 mg/d)
given concurrently during the first week of two split
courses of radiation (total dose 40 Gy)
Result showed trend towards improvement in OS but
not statistically significant
68. RESULTS
Patients who received chemoradiation did worse
median survival of 15.9 months
than those not receiving chemoradiation (median
survival of 17.9 months)
who received chemotherapy had a median survival of
20.6 months
69. The investigators concluded that chemoradiation not
only failed to benefit patients but also reduced
survival when given before chemotherapy.
70. FLAWS IN ESPAC 1
Physicians were allowed to choose which of the three
parallel trials to enroll patients on, creating potential
bias
Patients could receive background•chemoradiation
or chemotherapy as decided by their physician.
Approximately one third of the patients enrolled on
the chemotherapy versus no chemotherapy trial
received background chemoradiation therapy or
chemotherapy
71. The radiation was given in a split-dose fashion, with
the treating physician judging the final treatment
dose (40 Gy vs. 60 Gy).
In the chemoradiation versus no chemoradiation
trial, no maintenance adjuvant chemotherapy was
given
All these trials do not address local control,
palliation of local symptoms, and quality of life
75. With available studies role of RT in adjuvant setting
is not well established
Adjuvant chemotherapy has definite role in adjuvant
setting
It has been suggested patients with R1 resections or
positive lymph nodes may be more likely to benefit
from adjuvant chemoradiation.
76. To definitively clarify the role of chemoradiation
following gemcitabine monotherapy in the adjuvant
setting
RTOG is conducting trial 0848.
Patients without evidence of progressive disease
after 5 cycles of gemcitabine-based chemotherapy
are being randomized to 1 additional round of
chemotherapy
or 1 additional round of chemotherapy followed by
chemoradiation with capecitabine or 5-FU.
77. Neoadjuvant Therapy
Approximately 25% of patients do not receive
adjuvant therapy in a timely manner after surgery or
do not receive it at all
Given the high recurrence rates after surgical
resection, pancreatic cancer is likely a systemic
disease at the time of diagnosis in 80% to 85% of
patients who appear to have resectable disease
78. with neoadjuvant therapy, 20% to 40% of patients
will be spared the morbidity of resection
because their metastatic disease becomes clinically
apparent
Preoperative therapy could theoretically be less toxic
and more effective
Patients with local and unresectable lesions may be
able to be downstaged to allow for surgical resection
79. Potential disadvantages include the fact that
in the absence of staging laparoscopy, some patients with
distant metastatic disease who are unlikely to benefit
from RT will receive unnecessary treatment
it is possible that local progression during neoadjuvant
therapy will preclude surgical resection
radiation-related toxicity may impair the patient’s ability
to tolerate surgery
increase risk of wound complications.
80. analysis of preoperative vs. postoperative
chemoradiotherapy at M. D. Anderson Cancer
Center
did not note differences in toxicity or survival.
Evans et al reported results of a phase II study of 86
pancreas cancer patients with potentially resectable
disease treated with
preoperative chemoradiotherapy (7 weekly doses of
gemcitabine 400 mg/m2 plus 30 Gy radiation in 10
fractions)
81. The authors concluded that preoperative
gemcitabine-based chemoradiotherapy identified a
subgroup of patients unlikely to benefit from surgical
resection
Randomized trials are lacking, but existing data
support further exploration of neoadjuvant
chemoradiotherapy
82. UNRESECTABLE TUMORS
intermediate prognosis between resectable and
metastatic patients.
therapeutic options include
EBRT with 5-FU chemotherapy
IORT
EBRT with novel chemotherapeutic and targeted agents.
83. TRIALS
The Mayo Clinic undertook an early randomized trial
in the 1960s
64 patients with locally unresectable, nonmetastatic
pancreatic adenocarcinoma received 35 to 40 Gy of
EBRT with concurrent 5-FU versus the same EBRT
schedule plus placebo.
A significant survival advantage was seen for
patients receiving EBRT with 5-FU versus EBRT only
(10.4 months vs. 6.3 months)
85. with the exception of one study
conventional EBRT combined with 5-FU
chemotherapy has been shown to offer a modest
survival benefit for patients with locally advanced
unresectable pancreatic cancer compared to
radiation alone or chemotherapy alone
86. Intraoperative Radiation Therapy
Because of the poor local control and results achieved
with conventional EBRT and chemotherapy
increase the radiation dose to the tumor volume have
been used to improve local tumor control without
significantly increasing normal tissue morbidity
A lower incidence of local failure in most series and
improved median survival in some have been reported
with these techniques when compared with conventional
external beam irradiation
but it is uncertain whether this is due to superior
treatment or case selection
87. Chemoradiation Following
Chemotherapy in Locally Advanced
Disease
Starting with 2 to 6 cycles of systemic chemotherapy
followed by chemoradiation therapy is an option for
selected patients with unresectable disease and good
performance status who have not developed
metastatic disease.
88. it is highly unlikely that the patient will become
resectable (ie, complete encasement of superior
mesenteric/celiac arteries)
there are suspicious metastases
the patient may not be able to tolerate
chemoradiation
89. Employing an initial course of chemotherapy may
improve systemic disease control in these cases.
In addition, the natural history of the disease can
become apparent during the initial chemotherapy,
thus allowing the selection of patients most likely to
benefit from subsequent chemoradiation
90. CHEMOTHERAPY
Gemcitabine Monotherapy
In the large phase III CONKO-001 trial, in which 368
patients without prior chemotherapy or RT were
randomly assigned to adjuvant gemcitabine versus
observation
DFS 13.4 VS 6.9 months
An absolute survival difference of 10.3% was observed
between the two groups at 5 years (20.7% vs. 10.4%).
91. Gemcitabine Combinations
Gemcitabine has been investigated in combination
with potentially synergistic agents (such as cisplatin,
oxaliplatin, capecitabine, 5-FU, and irinotecan)
Two recent meta-analyses of randomized controlled
trials both found that gemcitabine combinations give
a marginal benefit in OS over gemcitabine
monotherapy in the advanced setting, with a
significant increase in toxicity
92. Combination with ERLOTINIB
phase III, double-blind, placebo-controlled NCIC
CTG PA.3 trial of 569 patients with advanced or
metastatic pancreatic cancer
randomly assigned to receive erlotinib plus
gemcitabine versus gemcitabine alone
patients in the erlotinib arm showed statistically
significant improvements?? in OS
MS 6.24 VS 5.91 months
93. Gemcitabine Plus Cisplatin
3 phase III trials evaluating the combination of
gemcitabine with cisplatin versus gemcitabine alone
in patients with advanced pancreatic cancer failed to
show a significant survival benefit for the
combination over the single agent
94.
95.
96. Gemcitabine dosage
1000 mg/m² intravenously over 30 minutes.
repeat at weekly intervals for up to 7 weeks, followed
by one week of rest.
If toxicity occurs, a dose should be held.
Subsequent cycles should consist of weekly cycles
for 3 consecutive weeks, out of every 4 weeks
Erlotinib -100-150 mg/day
97. FOLFIRINOX
(oxaliplatin, 85 mg per m2irinotecan, 180 mg per
m2; leucovorin, 400 mg per m2; and fluorouracil,
400 mg per square meter given as a bolus
followed by 2400 mg per square meter given as a 46-
hour continuous infusion, every 2 weeks
98. RT TECHNIQUES
Immobilisation
The patient lies supine in a vacuum moulded bag with
arms above the head in arm rests
CT scans are acquired as described above with a slice
thickness of 5 mm at 2–5mm
interslice intervals from the top of the liver or top of T11
to cover lymph nodes
to the lower border of L3 and/or kidneys.
99. CT-MRI fusion may be appropriate in some cases if
additional information is derived from an MR scan
Renal contrast is given and an initial anterior-
posterior (AP) and lateral films are taken to establish
the position of the kidneys.
oral contrast is given to visualize the stomach and
duodenal C-loop, which will localize the position of
the head of the pancreas
100. Target volume definition
For lesions of the head of the pancreas,
invade the medial wall of the duodenum, and
therefore the entire involved duodenal wall should
be covered for lesions
nodal groups should include the
pancreaticoduodenal, suprapancreatic, celiac, and
porta hepatis lymph nodes.
101. For lesions in the pancreatic body or tail
the target volume includes the tumor with a 2- to 3-
cm margin
pancreaticoduodenal and porta hepatis nodes, lateral
suprapancreatic nodes, and nodes of the splenic
hilum.
It is not necessary to include the whole duodenal
loop in the treatment field
102. Target volume definition
GTV which includes any enlarged regional lymph nodes
of 1.5 cm (GTV-T and -N)
The CTV should include visible tumour and surrounding
oedema
PTV margins are anisotropic with 5–10 mm in the AP
direction, 2–4 mm in the transverse plane
15–30 mm cranio-caudally to take account of organ
movement with respiration or gut motion
103. CONVENTIONAL FIELD BOARDERS
Superior and Inferior Borders
For pancreatic head lesions, to ensure adequate
coverage on the celiac nodes, the superior border
should be at the T10/T11 level
the lower border at the L3/L4 level, depending on
the preoperative staging studies
104. Lateral field boarder should include tumor with 2.5-
3 cm margin
Posteriorly should include 1.5-2 cm of vertebral body
Anteriorly to cover tumor with 1.5-2 cm margin
105.
106. OAR include the spinal cord, kidneys, liver and small
bowel.
107.
108.
109. RTOG GUIDELINES IN POST OP
Treatment Volumes: GTV
By definition there is no GTV (tumor has been resected)
Location of pancreatic tumor prior to resection must be
reviewed and contoured based on preoperative axial
imaging/simulation
Pre-operative diagnostic or simulation scans can be fused with
post-operative CT to facilitate localization of tumor bed
Surgical and pathological information must be reviewed at
time of treatment planning
110. CTV
The post operative CTV is that area where there is
likely tobe the highest concentration of residual sub-
clinical tumor
that can be treated with radiotherapy without
resulting in a treatment volume that encompasses an
excessive amount of normal organs and normal
tissue.
112. ROI Delineation:
CA and SMA
The most proximal 1.0-1.5 cm of the celiac artery
(CA)
The most proximal 2.5 to 3.0 cm of the superior
mesenteric artery (SMA
113. PV
Include the portal vein (PV) segment that runs slightly to
the right of, in front of (anterior) and anteromedial to the
inferior vena cava (IVC).
Contour from the bifurcation of the PV to, but do not
include, the PV confluence with either the SMV or
Splenic Vein (SV).
– The PV bifurcation can be extrahepatic or almost
intrahepatic.
– The PV most often will merge first with the SMV, but
may merge with the SV.
115. The pancreaticojejunostomy (PJ) is identified by
following the pancreatic remnant medially and
anteriorly until the junction with the jejunal loop is
noted.
The aorta (Ao) from the most cephalad contour of
either the celiac axis, PV, or PJ (whichever among
these 3 is the most cephalad) to the bottom of the L2
vertebral body.
If the GTV contour extends to or below the bottom of
L2 then contour the aorta towards the bottom of the
L3 vertebral body as needed to cover the region of
the preoperative tumor location
116. ROI Expansions
The celiac axis, SMA, and PV ROI’s should be
expanded by 1.0 - 1.5 cm in all directions..
The PJ should be expanded 0.5 -1.0 cm in all
directions.
Delineated clips may be expanded by 0.5 – 1.0 cm in
all directions or used without expansion
117. Suggested approximate expansion amounts for the
aortic ROI are as follows:
2.5 to 3.0 cm to the right
1.0 cm to the left
2.0 to 2.5 cm anteriorly
0.2 cm posteriorly towards the anterior edge of the
vertebral body
Goal is to cover paravertebral nodes laterally while
avoiding kidneys
118. The CTV should then be created by merging the
above ROI/ ROI expansions
CA, SMA, PV, GTV, Aortic, PJ, HJ, clips
124. Dose-fractionation
Radical (in combination with chemotherapy with
gemcitabine or 5FU)
45–50.4 Gy in 25–28 fractions of 1.8 Gy given in 5–
51⁄2 weeks.
125. Role of IMRT
Ben-Josef and colleagues described using an IMRT
approach to treat locally advanced and resected
pancreatic cancer with concurrent capecitabine
Using this technique, the primary tumor (or tumor bed if
treating postoperatively) was treated with 54 Gy and the
lymph nodes with 45 Gy
Acceptable toxicity occurred if the following dose
limitations were observed:
50% of each kidney below 20 Gy, 67% of liver below
35 Gy, 90% of small bowel below 45 Gy, 90% of stomach
below 45 Gy, and 90% of spinal cord below 45 Gy
Editor's Notes
High bmi increases risk
Eus or mri or mrcp
cystadenocarcinoma may run a much more indolent course
Patients with locally advanced disease with involved peritoneal washings or positive peritoneal biopsies have the same prognosis as those with metastatic disease.
