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 patientComorbiditiesperformance statusfrailty 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

DiseaseStarting 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 dosage1000 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 right1.0 cm to the left2.0 to 2.5 cm anteriorly0.2 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