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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 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