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CARCINOMA
PANCREAS
Anatomy
 The pancreas is an elongated, coarsely lobulated
gland lying transversely and retroperitoneally in the
posterior abdomen
 at approximately the L1 to L2 level
Arterial Supply
Venous Drainage
Lymphatic Drainage
Innervation
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
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
 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
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.
 95% of pancreatic adenocarcinomas contain k-ras
oncogenes activated by a mutation at codon 12.
 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
 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
 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
 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
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.
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
 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
 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
 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
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).
Evaluation
 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.
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
 (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
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
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
 WHEN?
 borderline resectable disease
 markedly elevated CA 19-9
 large primary tumors
 large regional lymph nodes
 highly symptomatic
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
 Pancreatic ductal brushings or biopsies can also be
obtained at the time of ERCP
STAGING
Diagnosis & staging
• Stage at Diagnosis
– 7% : Localized stage
• 5yr-SR = 20.3%
– 26% : +ve Regional LN involvment / T3 up
• 5yr-SR = 8.0%
– 52% : metastasis (Distant stage)
• 5yr-SR = 1.7%
– 15% : unknown stage information
• 5yr-SR = 4.1%
• Overall 5yr-SR = 5%
MANAGEMENT
 RESECTABLE
 BORDERLINE RESECTABLE
 UNRESECTABLE BUT NOT METASTATIC
 METASTATIC
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
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
UNRESCTABLE
Management of Resectable and
Borderline Resectable
Disease
 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
 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
 prognostic indicators for long-term patient survival
 Negative margin status (ie, R0 resection)
 Tumor DNA content
 tumor size
 absence of lymph node metastases
 When deciding whether a patient is a surgical
candidate.
 Age of the patient
 Comorbidities
 performance status
 frailty are all things to be discussed
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.
Surgical Procedures
 Tumors of the Body
and Tail
 Distal Pancreatectomy
 Removal of body & tail of
pancreas
 spleen
Surgical Procedures
 Head of the
pancreas: Whipple
Procedure
 Removal of:
 Distal stomach
 Duodenum and
proximal jejunem
 Head of pancreas
 Gallbladder and
common bile duct
Complications
 Whipple Procedure
 bleeding
 Gastroparesis
 Pancreatic duct leak
 Bile duct leak
 Diabetes
 malabsorption
 Distal pancreatectomy
 Bleeding
 Pancreatic duct leak
 Malabsorption
 diabetes
 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
 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
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
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
 It is considered
 When surgery is delayed due to sepsis
 When planned for neoadjuvant therapy
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.
PATTERN OF FAILURE
 the bed of the resected pancreas (local recurrence)
 the peritoneal cavity
 liver
 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
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
 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
 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
ESPAC 1 TRIAL
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
 The investigators concluded that chemoradiation not
only failed to benefit patients but also reduced
survival when given before chemotherapy.
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
 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
Studies of Gemcitabine-Based Adjuvant Therapy
 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.
 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.
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
 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
 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.
 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)
 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
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.
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)
RCT IN UNRESECTABLE TUMORS
 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
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
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.
 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
 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
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%).
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
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
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
 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
 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
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.
 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
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.
 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
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
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
 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
 OAR include the spinal cord, kidneys, liver and small
bowel.
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
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.
CTV
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
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.
Post-op Bed
 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
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
 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
 The CTV should then be created by merging the
above ROI/ ROI expansions
 CA, SMA, PV, GTV, Aortic, PJ, HJ, clips
CTV EXPANSION
NORMAL STRUCTURES
 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.
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

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pancreatic cancer management

  • 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
  • 3.
  • 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).
  • 26.
  • 27.
  • 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
  • 39.
  • 40. Diagnosis & staging • Stage at Diagnosis – 7% : Localized stage • 5yr-SR = 20.3% – 26% : +ve Regional LN involvment / T3 up • 5yr-SR = 8.0% – 52% : metastasis (Distant stage) • 5yr-SR = 1.7% – 15% : unknown stage information • 5yr-SR = 4.1% • Overall 5yr-SR = 5%
  • 41. MANAGEMENT  RESECTABLE  BORDERLINE RESECTABLE  UNRESECTABLE BUT NOT METASTATIC  METASTATIC
  • 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
  • 45. Management of Resectable and Borderline Resectable Disease
  • 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
  • 53.
  • 54. Complications  Whipple Procedure  bleeding  Gastroparesis  Pancreatic duct leak  Bile duct leak  Diabetes  malabsorption  Distal pancreatectomy  Bleeding  Pancreatic duct leak  Malabsorption  diabetes
  • 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
  • 67.
  • 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
  • 72. Studies of Gemcitabine-Based Adjuvant Therapy
  • 73.
  • 74.
  • 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.
  • 111. CTV
  • 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
  • 119.
  • 120.
  • 123.
  • 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

Notas do Editor

  1. High bmi increases risk
  2. Eus or mri or mrcp
  3. cystadenocarcinoma may run a much more indolent course
  4. Patients with locally advanced disease with involved peritoneal washings or positive peritoneal biopsies have the same prognosis as those with metastatic disease.
  5. PANCREAS AND DUODENUM SHARE SAME VESSELS
  6. 2020