This document summarizes the management of pancreatic carcinoma. It discusses the anatomy, epidemiology, risk factors, hereditary syndromes, pathophysiology including pre-cancerous lesions, types of pancreatic cancer, staging, prognostic factors, diagnostic techniques, treatment including surgery, chemotherapy, targeted therapy, radiotherapy and historical prospective studies. It provides a comprehensive overview of pancreatic carcinoma covering all relevant aspects of the disease.

1. Management of Carcinoma Pancreas
Dr Kiran Kumar BR

2. ANATOMY

3. Regional drainage
Pancreatic head :
peripancreatic,
pancreaticoduodenal,
porta hepatis,
celiac, and superior mesenteric lymph nodes.
Pancreatic body and tail :
splenic artery,
peripancreatic,
celiac,
superior mesenteric,
paraaortic nodal basins.

4. EPIDEMIOLOGY
• There were 460,000 new cases in 2018 worldwide.
• In comparison to the West, India has a relatively lower
incidence of pancreatic cancer.
• The rates in India vary from 0.5 to 2.4/1lac persons per
year among women to 0.2 to 1.8/1 lac persons per year
among men.
• The National Cancer Registry Programme has
estimated that by 2020, there will be 8440 and 6090
new cases of pancreatic cancer afflicting Indian men
and women, respectively.

6. Risk Factors
1.Age
2.Sex.
3.Ethnicity.
4.Cigarette smoking.
5.Obesity.
1.Family history.
2.Chronic pancreatitis: almost
triple risk.
3.Diabetes mellitus
4.Dietary factors.
5.Helicobacter pylori infections.
Drinking alcohol excessively is a major cause of chronic
pancreatitis

7. Hereditary syndromes
• Peutz–Jeghers syndrome- due to mutations in the STK11 tumor
suppressor gene.
• Dysplastic nevus syndrome (or familial atypical multiple mole and
melanoma syndrome, FAMMM-PC) due to mutations in the CDKN2A
tumor suppressor gene.
• Autosomal recessive ataxia-telangiectasia and autosomal
dominantly inherited mutations in the BRCA2 gene and PALB2 gene.
• Hereditary non-polyposis colon cancer (Lynch syndrome) and
familial adenomatous polyposis.
• PanNETs have been associated with multiple endocrine neoplasia
type 1 (MEN1) and von Hippel Lindau syndromes.

8. Pancreatic intraepithelial
neoplasia
Intraductal papillary
mucinous neoplasms
Microscopic abnormalities in the
pancreas
May progress from low to high
grade and then to a tumor.
More than 90% of cases at all grades
carry a faulty KRAS gene.
Macroscopic lesions, which are
found in about 2% of all adults.
This rate rises to ~10% by age 70.
Have about a 25% risk of
developing into invasive cancer.
May have KRAS gene mutations
(~40–65% of cases)
Pathophysiology
Precancer

9. Pancreatic mucinous cystic
neoplasms (MCNs)
Intraductal tubulo-papillary
neoplasm
Mainly occur in women,
May remain benign or progress to
cancer.
If these lesions become large, cause
symptoms, or have suspicious
features, they can usually be
successfully removed by surgery.
Recognized by the WHO in 2010 and
constitutes about 1–3% of all
pancreatic neoplasms.
Mean age at diagnosis is 61 years.
About 50% of these lesions become
invasive.
Diagnosis depends on histology as
these lesions are very difficult to
differentiate from other lesions.
Pathophysiology
Precancer

10. Invasive cancer
Four genes have each been found to be mutated in the majority of
adenocarcinomas:
 KRAS (in 95% of cases).
 CDKN2A (also in 95%).
 TP53 (75%).
 SMAD4 (55%).
• SWI/SNF mutations/deletions occur in about 10–15% of the
adenocarcinomas.

11. PanNETs
• The genes often found mutated in PanNETs are different from those in
exocrine pancreatic cancer.
• MEN 1 gene mutation.
• About 40–70% of people born with a MEN1 mutation eventually
develop a PanNet.
• Other genes that are frequently mutated include DAXX, mTOR and
ATRX.

12. Exocrine component. Pancreatic neuroendocrine
tumors
1. The vast majority of cases (about
95%)
2. Pancreatic adenocarcinoma
3. most common type, about 85% of all
pancreatic cancers.
4. Nearly all these start in the ducts of
the pancreas, as pancreatic ductal
adenocarcinoma (PDAC).
5. About 60–70% of adenocarcinomas
occur in the head of the pancreas.
6. Acinar cell carcinoma ,
Cystadenocarcinomas,
Pancreatoblastoma.
1. Functioning' and ‘Non-functioning'
types
2. The functioning types secrete
hormones such as insulin, gastrin, and
glucagon into the bloodstream, often
in large quantities
3. Gives rise to serious symptoms such
as low blood sugar, but also favors
relatively early detection.
4. The most common functioning
PanNETs are insulinomas and
gastrinomas.
Types: Both groups occur mainly (but not exclusively) in
people over 40

13. Signs and symptoms
• Pain in the upper abdomen or back, often spreading from around the
stomach to the back.
• Jaundice.
• Unexplained weight loss, either from loss of appetite.
• At least 50% of people with pancreatic adenocarcinoma have diabetes
at the time of diagnosis.
• Trousseau's syndrome: blood clots form spontaneously in the portal
blood vessels, the deep veins of the extremities, or the superficial
veins anywhere on the body, found in about 10% of cases.

14. Diagnosis
• High-resolution pancreatic CT and EUS remain the current standard
for diagnosis and staging of pancreatic malignancies.
Multiphasic CT scan:
This allows for adequate imaging
• of the pancreas and assessment of metastatic deposits in other intra-
abdominal organs such as the liver.
• limited in detection of nodal involvement and peritoneal disease
• useful in evaluating for metastatic disease.

15. • A Pancreatic protocol is used during the CT image acquisition.
• Under this, iv contrast is administered and a triphasic scan is performed.
The three phases are:
• Early arterial phase - 15-20 sec.
For delineating arterial structures like celiac artery and SMA.
• Pancreatic (late arterial); - 35-40 sec.
Maximal differentiation between the normal parenchyma and hypodense
pancreatic tumors like adenocarcinoma.
• Portal venous- 70-80 sec.
Metastases in the liver are best detected at 70-80 sec when the liver
parenchyma enhances optimally.

16. Endoscopic
ultrasound
MRI PET CT
An endoscope with an
ultrasound transducer at
its tip is passed into the
stomach and duodenum,
where it provides high-
resolution images of the
pancreas and surrounding
vessels.
An advantage of EUS
over CT is the ability to
detect small lesions.
Staging laparoscopy has
been used
preoperatively to assess
for intraperitoneal
metastases.
Three-dimensional (3D)
reconstruction, functional
imaging, and MR
cholangiopancreatography,
have led to an improved
ability of MRI to diagnose
and stage pancreatic cancer.
In patients with poor renal
function to assess the
primary tumor and
determine resectability;
Not as sensitive as EUS or
CT in tumor detection.
Integrated
PET-CT had a higher
sensitivity for malignancy
detection than did either
PET or
CT alone (96% vs. 84% vs.
77%) but did not improve
specificity (64%).

17. • Liver function tests can show a combination of results
indicative of bile duct obstruction (raised conjugated bilirubin,
γ-glutamyl transpeptidase and alkaline phosphatase levels).
• CA19-9 (carbohydrate antigen 19-9) is a tumor marker that
is frequently elevated in pancreatic cancer. However, it lacks
sensitivity and specificity, because 5% of people lack the
Lewis antigen and cannot produce CA19-9.
• It has a sensitivity of 80% and specificity of 73% in detecting
pancreatic adenocarcinoma, and is used for following known
cases rather than diagnosis.

18. AJCC Staging

20. To help decide treatment, the tumors are also divided into

21. Criteria for Resectability

22. Prognostic Factors:
Positive operative margins,
Poor histologic grade,
Larger tumor size,
Lymphovascular invasion,
Lymph node involvement.
CA19-9

23. Treatment
• Surgery represents the only potentially curative treatment
strategy.
• Head or uncinate : pancreaticoduodenectomy or Whipple's
procedure.
• Pancreatic tail lesions, distal pancreatectomy is employed,
frequently with splenectomy.
• 12 to 15 lymph nodes constitute an adequate assessment

25. Chemotherapeutic agents

26. Chemotherapy Regimen
• Gemcitabine 100mg/m2
• Capecitabine 1200mg/m2.
Targeted therapy:
Erlotinib
Cetuxiamb

27. Radiotherapy
 Resectable/borderline resectable
 Resected (adjuvant)
 Locally advanced
 Palliative
 Recurrent

28. Dose and Fractionation
Resectable/Borderline Resectable (Neoadjuvant):
• 36Gy in 2.4Gy fractions to 45–54Gy in 1.8–2.0Gy fractions
Resected (Adjuvant):
• 45–46Gy in 1.8–2.0Gy fractions to the tumor bed, surgical
anastomoses and adjacent lymph node basins,
• Potentially followed by an additional 5–9Gy to the tumor bed
and anastomoses, if clinically appropriate.
• Escalation above 54Gy should ideally be avoided or used only in
a clinical trial.

29. Locally Advanced (Definitive):
45–54Gy in 1.8–2.0Gy fractions.
Doses higher than 54Gy may be considered on a clinical trial.
There are limited data to support a specific RT dosing for SBRT;
preferably be utilized as part of a clinical trial or at an
experienced, high-volume center.
SBRT doses of 3 fractions (total dose 30–45 Gy) or 5 fractions
(total dose 25–45 Gy) have been reported.

30. SBRT
• Involves the delivery of high dose per fraction radiation
treatments over a small number of fractions (generally 1 to 5
treatments), utilizing techniques that allow very highly
conformal dose delivery of external beam radiotherapy.
• Potentially improving local control through the delivery of
ablative doses of radiation, while minimizing associated side
effects.
• A report from these investigators described 77 patients who
were treated with SBRT and found that freedom from local
progression was 91% at 6 months and 84% at 12 months.
• A meta-analysis of 19 studies encompassing over 1,000
patients treated with SBRT demonstrated a 1-year local control
rate of 72%.

31. RADIATION THERAPY TECHNIQUES
Position:
Supine with arms up in an Alpha Cradle or equivalent immobilization
device custom-made for each patient.
Simulation:
• Ideally, placement of 1–5 (preferably ≥3) gold fiducial markers.
• Placement of fiducial markers directly into the tumor and/or periphery
under EUS is preferred.
• Stents can assist with targeting; however, they can shift and are
therefore less reliable than fiducials.
Scan range:
• T4/T5 to L5/S1 (upper abdomen).
• CT simulation (2- to 3-mm slices) should be performed with IV
(assuming adequate kidney function) and oral contrast.

32. Motion Management:
• Respiratory motion should be accounted for determining the internal
target volume (ITV).
• This may be accomplished utilizing a 4D-CT scan.
• Motion management using respiratory gating or breath-hold,
respiratory tracking, or abdominal compression may be used to reduce
cranio-caudal tumor/fiducial marker motion, typically reducing from
an 11- to 22-mm peak to ≤5 mm.
Treatment Volumes and Fields:
• Surgical clips should be placed to mark the extent of the lesion for
postoperative irradiation.
• Multiple field, fractionated, external beam techniques utilizing high-
energy photons to deliver 45 to 50Gy in 1.8Gy fractions to tumor bed,
unresected or residual tumor, and lymph node–bearing areas at risk.

33. Approximately two-thirds of the left kidney must be excluded from
the AP/PA field because the right kidney is often in the field
because of duodenal (bed) inclusion.
The superior field extent : middle or upper portion of the T11
vertebral body for adequate margins on the celiac vessels (T12, L1)
Inferior limit at the level L2–L3 to include the superior mesenteric
lymph nodes and third portion of the duodenum.
The upper field extent is sometimes more superior with body
lesions to obtain adequate margin on the primary lesion.

34. Lateral fields, the anterior field margin is 1.5 to 2.0 cm beyond initial
gross disease.
The posterior margin is 1.5 cm behind the anterior portion of the
vertebral body to allow adequate margins on paraaortic nodes
The lateral contribution usually is limited to 15 to 18Gy because a
moderate volume of kidney or liver may be in the irradiated volume

37. Contouring Guidelines
Post-op case
• CTV:
 Post-operative bed
• Based on location of initial tumor from pre-operative imaging and
pathology
 Anastomoses
• Pancreaticojejunostomy(PJ)
• Choledochal or hepaticojunostomy
 Abdominal nodal regions
• Peripancreatic
• Celiac
• Superior mesenteric
• Porta hepatis
• Para-aortic

39. Organ at
Risk
(OAR)
Neoadjuvant/Definitive/Palliati
ve and
Recurrent Recommendations
Adjuvant Recommendationse
Kidney
(right and
left)
Not more than 30% of the total
volume can receive ≥18 Gy.
For 3D conformal plans in patients with two normally functioning
kidneys, at least 50% of the right kidney and at least 65% of the
left kidney must receive <18 Gy.
For IMRT planning, mean dose to bilateral kidneys must be <18
Gy. If only one kidney is present, not more than 15% of the
volume of that kidney can receive ≥18 Gy and not more than 30%
can receive ≥14 Gy.
Stomach
,
duodenu
m,
jejunum
Max dose 55 Gy.
<15% of the volume of each organ can receive between 45 and
49.99 Gy.
Liver Mean dose cannot exceed 30
Gy.
Mean liver dose must be ≤25 Gy.
Spinal cord Max dose to a volume of at
least 0.03 cc must be ≤45 Gy.
Max dose ≤45 Gy.
Organs at Risk

40. • The CONKO 001 trial demonstrated significant improvements in
DFS and OS with use of postoperative gemcitabine as adjuvant
chemotherapy versus observation in resectable pancreatic
adenocarcinoma.
• ESPAC-3 study results showed no significant difference in OS
between 5-FU/leucovorin versus gemcitabine following surgery.
When the groups receiving adjuvant 5-FU/leucovorin and adjuvant
gemcitabine were compared, median survival was 23.0 months and
23.6 months, respectively.
• Data from ESPAC-4 support the use of gemcitabine
combined with capecitabine (1,660 mg/m2/day days 1–21
every 4 weeks) with superiority demonstrated compared to
gemcitabine alone (HR, 0.82; 95% CI, 0.68, 0.98; P = .032).3
• No significant differences were observed in the RTOG 97-04
study comparing pre- and post-chemoradiation 5-FU with pre-
and post- chemoradiation gemcitabine for postoperative
adjuvant treatment.4

41. Historical Prospective Studies
The gastrointestinal tumor study group (GITSG)
• Multicenter prospective trial
• Resected pancreatic cancer and negative surgical margins,
• Forty-three patients
• Randomized to observation or CRT to 40 gy delivered in split-
course fashion with concurrent 5- fluorouracil (5-FU) (500 mg/m2)
as an intravenous bolus on the first 3 and last 3 days of radiation,
followed by maintenance weekly 5-FU for 2 years or until disease
progression.

42. • European Organisation for Research and Treatment
of Cancer (EORTC)
• Two hundred eighteen patients with resected
pancreas or periampullary cancers
• Randomly assigned to observation or CRT to 40 Gy
in a split-dose fashion with concurrent continuous
infusional 5-FU (25 mg/kg) without further adjuvant
chemotherapy

43. • European trial conducted by the European Study Group for Pancreatic
Cancer (ESPAC)
“Macroscopically” resected pancreatic cancers.
• Treating physicians were allowed to enroll patients into one of three
parallel randomized studies:
 Chemoradiation versus no chemoradiation
20Gy over 2 weeks with 5-FU (500 mg/m2) on days 1 through 3, then
repeated after a 2- week break.
 Chemotherapy versus no chemotherapy
bolus 5-FU(425 mg/m2) and leucovorin (20 mg/m2) given for 5 days
every 28 days for 6 cycles.
 A 2-by-2 factorial design of 285 patients enrolled on
chemoradiotherapy, chemotherapy, chemoradiotherapy with
maintenance chemotherapy, or observation.

44. • No survival difference between the patients who received
adjuvant chemoradiation and the patients who did not receive
therapy (median survival, 15.5 vs. 16.1 months; P=.24).
• In the chemotherapy arm, however, a 35% reduction in death
was seen in the group who received adjuvant chemotherapy
compared with those who received no chemotherapy, with a
difference in median survival of 19.7 versus 14 months (P =
.0005).
• On further follow-up of patients randomized using the 2-by-2
factorial design, the 5-year survival rate for the patients who
received chemotherapy was 21% versus 8% for those who did
not.
• Additionally, adjuvant CTRT was associated with
a deleterious effect on survival

45. • A common critique of the aforementioned trials:
Lack of restaging to evaluate for the presence of persistent or metastatic
disease after surgical resection and prior to the initiation of adjuvant
therapy.
The time between initial staging and the commencement of adjuvant
treatment was sometimes as long as 3 to 4 months,
during which a significant number of patients would be expected to
develop radiographically apparent metastases.
Without interval restaging, these patients may inappropriately receive
CRT

46. Modern Studies
Adjuvant Systemic Therapy
• Conko
Three hundred sixty-eight patients were enrolled on the charite
onkologie (conko) trial
Randomized to:
• Observation or
• Adjuvant gemcitabine (1,000 mg/m2 intravenous days 1, 8, and 15
every 4 weeks for 6 months).
The primary end point was dfs, and patients treated with gemcitabine
achieved a statistically significantly longer dfs (14.2 vs. 7.5 months)
than those observed after surgery.
• This improvement was seen in both the r0 and r1 subgroups.

47. Espac-3
Largest randomized controlled trial in pancreatic cancer to date,
• Enrolled 1,088 patients with pancreatic adenocarcinoma who
underwent R0 or R1 resection.
Patients were randomly assigned to :
• 6 cycles of adjuvant gemcitabine (3 weekly infusions of 1,000
mg/m2) or
• 6 cycles of bolus 5-FU (425 mg/m2)/leucovorin (LV) (20 mg/m2).
• Patients receiving 5-fu/lv experienced significantly higher rates of
grade 3 or 4 gastrointestinal toxicity (stomatitis and diarrhea),
whereas patients receiving gemcitabine experienced significantly
higher rates of grade 3 or 4 hematologic toxicity.
• At a median follow-up of 34.2 months, there was no difference
between the two groups in the primary end point of OS

48. ESPAC-4 trial
Randomized patients with resected pancreatic cancer to:
• Gemcitabine alone versus
• Gemcitabine/capecitabine.
Primary end point of overall survival.
The median survival for patients receiving adjuvant gemcitabine
and capecitabine was 28 months compared to 25.5 months in
the gemcitabine-alone arm.
Estimated overall survival was
Gemcitabine group: 80.5% at 12 months and 52.1% at 24
months
Gemcitabine plus capecitabine group : 84.1% at 12 months and
53.8% at 24 months.

49. Modern Studies: Adjuvant
Chemoradiation
Rtog/gastrointestinal intergroup trial 9704
Phase iii randomized study
Comparing adjuvant 5- fu–based chemotherapy to gemcitabine-based chemotherapy,
with both regimens followed by CRT.
Four hundred fifty-one patients with resected pancreatic cancer were randomized to
• Continuous infusion 5-fu (250 mg/m2/d)
• Or gemcitabine (1,000 mg/m2 weekly) for 3 weeks prior to CRT and 12 weeks after
CRT.
Crt in both groups consisted of 50.4 gy delivered with continuous
Infusion 5-FU (250 mg/m2/d)

50. Median and 5-year OS rates
Pancreatic head tumors of 20.5 months and 22% in those who received
Gemcitabine,
Compared with 17.2 months and 18% in those who received 5-FU.
On multivariate analysis, in the subgroup of patients with pancreatic head
lesions who received gemcitabine, there was a non significant trend toward
improved os (p = .08).
A secondary aim of rtog-9704 was to assess the ability of postresection
CA19-9 levels to predict survival.
When ca19-9 levels were analyzed in a cohort of 385 patients as a
dichotomized variable (<180 iu/ml vs. ≥180 IU/ml, ≤90 IU/ml vs. >90 IU/ml),
Significant survival difference favoring patients with CA19-9 levels of <180
IU/ml.
This corresponded to a 72% reduction in the risk of death

51. Neoadjuvant Chemoradiation
No phase III randomized trials of neoadjuvant CRT in resectable pancreatic
lesions have been conducted
vast majority of data come from phase II and retrospective studies
A review of the Surveillance, Epidemiology, and End Results (SEER) database
supports the use of neoadjuvant treatment.
This analysis included 3,885 patients treated for resectable pancreatic cancer:
• 70 patients (2%) received neoadjuvant EBRT,
• 1,478 (38%) received adjuvant EBRT,
• 2,337 (60%) weretreated with surgery alone.
Median OS was
• 23 months in patients receiving neoadjuvant EBRT,
• 17 months with adjuvant EBRT,
• 12 months in the surgery-alone cohort.

52. Pancreatic neuroendocrine tumor

53. • Some specific differences in treatment:
In functioning PanNETs,
• Octreotide is usually recommended prior to biopsy or surgery
• but is generally avoided in insulinomas to avoid profound
hypoglycemia
PanNETs in Multiple endocrine neoplasia type 1 are often multiple, and
thus require different treatment and surveillance strategies.
Chemotherapy: Combinations of several medicines have been used,
such as doxorubicin with streptozocin and fluorouracil (5-FU) and
capecitabine with temozolomide.
Targeted therapy : Everolimus and Sunitinib : for treatment of
progressive neuroendocrine tumors of pancreatic origin in patients with
unresectable, locally advanced or metastatic disease.

54. • Thank you.