INTRODUCTION…………………………………………………………… 2 GENERAL REVIEW Chapter 1 – 1.1 The importance of the current… [629375]

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TABLE OF CONTENTS

INTRODUCTION…………………………………………………………… 2

GENERAL REVIEW
Chapter 1 –
1.1 The importance of the current thesis ……………………………….. 4
1.2 More information about the focus of the current thesis …………..5

Chapter 2 – Pancreatic cancer management
2.1. More information on the cancer of the head of the pancreas …. 7
2.2. Current management of pancreatic cancer……………………. 8

Chapter 3 – Concurrent studies on the subject at hand
3.1. Evaluation of current studies concerning pancreatic head resection ………….. 10
3.2. Evaluation of current studies concerning vascular resection

Chapter 4 – Conclusions on current studies

SPECIAL REVIEW
CHAPTER 2: METHODOLOGY …………………… …………………………………… 11
2.1. Introduction ~ 5%
2.2. Materials and methods 15 – 25%
2.3. Results 40 – 50% of the special review
2.4. Discussion 20 – 30%
2.5. Conclusions ~ 5%

BIBLIOGRAPHY

APPENDIX A: QUESTIONNAIRE FOR PARTICIPANTS

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Introduction

This might sound a bit odd, but as a medical student, t he pancreas has always been
among my favourite organs. It has several functions. It is an endocrine gland ( which means that
it produces hormones that are secreted into the internal envir onment: insulin and to be more
precise ), as well as an exocrine gland ( it produces substances released into the exterior). When
the endocrine cells malfunction, diabetes follows : a common but treatable illness , albeit causing
difficulties in the patient’s everyday life due to the dietary restrictions and the strict medical
protocols to avoid diabetic ketoacidosis . The other serious diseases affecting the pancreas have
a much lower profile.
Pancreatic cancer, like the other so -called “silent” cancers (ovarian is another), tends to
present late, which accounts for its poor prognosis. A small tumor in the pancreas is rarely painful
or disruptive, especially if it grows in the tail. By the time it has grown large enough to cause
symptoms though , such as nausea, weight loss, pain or jaundice (from a tumor blocking the
common bile duct), it has often invaded nearby structures, or spread elsewhere in the body – as
happened to the actor Patrick Swayze or the Apple genius Steve Jobs . Once it has spre ad, the
disease is inoperable . This very fact about pancreatic cancer made me very interested in studying
it.
Pancreatic cancer is, in fact, the fourth most common cause of death due to cancer
worldwide. Throughout the years, according to research , the mortality rates have increased. More
specifically : In 2015, there will be 367,411 new cases and 359,335 deaths from it globally.
Pancreatic cancer causes about 4.0% of all cancer deaths. In addition, it is an aggressive type of
cancer and 80% of pat ients have locally advanced or metastatic pancreatic cancer at the time of
diagnosis. The median survival time for these patients is 4 months and that with metastatic
disease is only 2 to 3 months. Sadly, the overall survival rate for patients with pancrea tic cancer
has not improved over the past two decades1. Given the increasing rates of pancreatic cancer,
one can’t help but find this field of research on pancreatic carcinoma extremely interesting. The
current state of research in this field concerning pa ncreatic carcinoma is rather large , however
not much research has been done concerning pancreatic head carcinoma and even more
specifically whether vascular resection decreases the morbidity and mortality of patients or not.
In the first part of my thesis, the general review, I will first discuss the importance of my thesis ,
why I believe it is important to add it to the scientific literature concerning pancreatic head
carcinoma. Then, in the upcoming chapter s, I will compile, interpret and criticall y evaluate some
of the most outstanding, recent studies that have been conducted about the matter in hand to set
a solid foundation and I will follow up with p roblems that are still unsolved (controversies about
the subject) . During the second part of my thesis , the special review, I will proceed in presenting

1 Zhang Q, Zeng L, Chen Y, et al. Pancreatic Cancer Epidemiology, Detection, and Management. Gastroenterology Research and
Practice. 2016;2016:1 -10. doi:10.1155/2016/8962321

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the data that were collected from the Medicina 3 clinic during the years 2015 -2019 and in
continuation, I will proceed in interpreting my results.

At this point, I would like to sincerely thank my thesis coordinator, Dr. Doru Munteanu for guiding
me throughout this studious journey and for being kind and understanding and always available
to give me advice and take the time to answer my questions, as well as my parents and sister for
always standin g by my side and supporting me. I would also like to thank you, sir or madame, for
taking the time to read what I hope to be a small yet undoubtedly significant stepping stone in the
ongoing research for pancreatic cancer and my future medical career.

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GENERAL REVIEW

Chapter 1
1.1. The importance of the current thesis
As I mentioned previously, the current state of research in th e scientific field concerning
pancreatic head carcinoma is rather large, however not much research has been done concerning
whether vascular resection decreases the morbidity and mortality of patients or not. More
specifically.
Worldwide, the incidence of pancreatic carcinoma seems to increase, however, there are
large variations. In the United States, every year, 112,000 Americans die of gastrointestinal
cancer and the carcinoma of the pancreas accounts for 22% of these deaths (American cancer
society, 1991). In Germ any, the incidence ranges between 9 and 10 patients per 100,000
inhabitants and is the 6th leading cause of carcinoma -related death. In Japan, the incidence of
pancreatic carcinoma has sharply risen from 1.8 per 100,000 inhabitants in the Sixties to 5.2 in
the Mid -Eighties (Hirayama, 1989). In contrast, in India, Kuwait and Singapore, the rate is less
than 2.2 per 100,000 inhabitants and has remained stable over the last 20 years
Many possible risk factors have been discussed without being though abl e to pinpoint an
exact cause, as is usually the case with cancer. The cause for the onset of pancreatic cancer
remains unknown but several environmental factors have been found to be associated with it.
This association, however, is only firmly established for the following: Occupational exposure to
employees of manufacturing plants handling benzidine, gasoline derivatives or 2 -naphtalamine
have shown in retrospective studies to carry a 5 -fold increased risk of acquiring pancreatic cancer
(Bardin et al., 19 97; Selenskas et al., 1995; Tomenson et al., 1997; Yassi et al., 1994). Another
risk factor which has been discussed very controversial over the last years, is cigarette smoking.
Multiple cohort and case control studies have found that the relative risk of pancreatic cancer in
smokers is at least 1.5. This risk increases with the amount of cigarette consumption.
Large epidemiological studies also identified the presence of chronic pancreatitis what about
a 4-fold increased risk of acquiring pancreati c cancer in the further course (Lynch et al., 1996;
Lowenfels et al., 1997; Andren et al., 1997) .2 Other risk factors have been found to be diabetes
mellitus, as well as ethnicity. African -Americans have a higher incidence of pancreatic cancer
compared to individuals of Asian, Hispanic or Caucasian descent. There is also a higher incidence
of pancreatic cancer among Ashkenazi Jews, possibly due to a gene mutation involving the breast
cancer BRCA gene .
Other factors that have been linked to pancreatic cancer are : Having certain hereditary
conditions, such as : Multiple endocrine neoplasia type 1 (MEN1) syndrome , Hereditary
nonpolyposis colon cancer (HNPCC; Lynch syndrome) , von Hippel -Lindau syndrome , Peutz –

2 Birk D, Beger HG. Pancreatic cancer. Nih.gov. https://www.ncbi.nlm.nih.gov/books/N BK6961/. Published 2015.
Accessed May 23, 2019.

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Jeghers syndrome , Hereditary breast and ovari an cancer syndrome and Familial atypical multiple
mole melanoma (FAMMM) syndrome.
What makes pancreatic cancer a “silent cancer” is that it does not give many symptoms, if
any. I will mention some of the most common signs and symptoms, but as one ca n easily tell,
those are very nonspecific : jaundice (yellowing of the skin and whites of the eyes) , light-colored
stools , dark urine , pain in the upper or middle abdomen and back , weight loss for no known
reason , loss of appetite or feeling very tired. The fact that t he pancreas is hidden behind other
organs such as the stomach, small intestine, liver, gallbladder, spleen, and bile ducts makes the
diagnosis of pancreatic cancer even trickier.
There are treatments available nowadays, but as with most if not all types of cancer, staging
is what will define the prognosis. And given how pancreatic cancer does not “get caught” early,
the prognosis is rather bad. The median survival for untreat ed advanced pancreatic cancer is
about 3 1/2 months . The median survival duration from diagnosis with chemotherapy medical
treatment in locally advanced cancer of the pancreas has been reported as 6 to 12 months.
Patients with neuroendocrine tumors tend to have a much more favorable prognosis than, for
example, those with adenocarcinoma of the pancreas. The prognosis for those who are able to
have surgery is improved over those who are not able. Unfortunately, according to recent studies,
only about 15% of those individuals with pancreatic cancer will be found to be eligible for surgery
– for most, the cancer will have been found to be too advanced. For example, patients with
pancreatic cancer who received the Whipple surgical procedure in one study (from a very
experienced Johns Hopkins team) were reported as having a 21% five -year survival rate, with a
median survival of 15.5 months. In more recent studies this five -year median survival duration
after surgery has been reported as high as twenty months.
Upon evaluating these statistics, it would be fair to conclude that since we are dealing with
low survival rates, even a small increase of percentage to increase them can be proven to be
lifesaving. Hence, the reason for this thesis being, seeing if vas cular resection can be proven to
increase the morbidity and mortality in pancreatic head carcinoma resection.

1.2. More information about the focus of the current thesis
Since t he main type of cancer that affects the pancreas is the ductal adenocarcinom a, my
thesis will focus especially on that. PDAC (Pancreatic Ductal Adenocarcinoma) is an epithelial
tumor that arises from the cells of the pancreatic duct or ductules , for which it is named. In health,
the pancreatic duct(s) serve as the conduit through which digestive enzymes and bicarbonate ion
produced in acinar cells reach the small intestine. Ductal cells and acinar cells together represent
the “exocrine” pancrea s, from which the vast majority of pancreatic neoplasms arise.
PDAC growth is now thought to take place over an expanded period of time and is probable
to follow a step -by-step progression comparable to other carcinomas (especially colorectal
carcin oma). This progression is characterized by the transition of a normal pancreatic duct to a
pre-invasive precursor lesion known as pancreatic intraepithelial neoplasia (PanIN), which can

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ultimately develop into an invasive PDAC . The gradual accumulation of genetic mutations
stimulates this development. One of the most common and earliest discovered in PDAC is a
mutation in K -ras oncogene that occurs in 90 percent of instances. Other common genetic
mutations commonly found in PDAC include activation of onco genic Her -2/neu, and loss of
function in tumor suppressor genes such as p16, p53, and SMAD434.
As mentioned, earlier pancreatic cancer is in general a silent cancer, however, tumors arising
from the head of the pancreas due to the fact that it conta ins the common bile duct, give clinical
symptoms earlier on. A tumor that causes obstruction of the common bile duct causes, what is
called, “painless jaundice” as bile accumulates in the blood, which will make a tumor there more
apparent in imaging studie s. PDAC might also cause acute pancreatitis (due to the pancreatic
duct obstruction). New onset diabetes in an adult patient that is otherwise healthy is also an
uncommon presentation of PDAC, though it is also one that carries a poor prognosis.
The presenting symptoms and signs discussed above are not specific for the diagnosis of
PDAC, and therefore a diagnosis of PDAC can only be made after further investigation such as
laboratory tests and of course imaging studies. Once a diagnosis of PDAC is c onfirmed or highly
suspected, an attempt to stage the tumor is made. This is achieved primarily through triphasic
CT scan of the abdomen . The tumor marker carbohydrate antigen 19 -9 (CA 19 -9) may be
increased in 75 -85% of patients with PDAC. It is non -specific and may be elevated in benign
biliary or pancreatic disease, nor is it perfectly sensitive. Therefore while an elevated CA 19 -9 in
a patient with a pancreatic mass is highly suspicious for PDAC, it does not make the diagnosis.
Rather, the role of C A 19-9 is predominantly one to assess for recurrence after surgery 5.
Surgical resection remains the only definitive treatment for PDAC, and the only treatment that
offers a chance for cure. For PDAC located in the head of the pancreas, a
pancreatic oduodenectomy (also known as a “Whipple” procedure) is the only surgery of choice ,
as will be mentioned later on as well. Although historically plagued by high operative mortality,
the Whipple procedure is now performed safely with perioperative mortality around 2% when
performed by a surgeon in a high -volume center. However, between 30 -40% of patients will
endure a major complication, most commonly pancreatic fistula or delayed gastric emptying 6.
Currently, overall 5 -year survival is 7.2% for pati ents with PDAC, meaning that 7.2% of all
patients diagnosed with PDAC are expected to be alive 5 years after diagnosis. The subset of
patients that have “localized” disease (and therefore are surgical candidates) may expect a 27.1%
5-year survival. This d iscrepancy is a testament to the fact that surgery remains the only truly
effective treatment modality.

3 Hruban RH, Goggins M, Parsons J, Kern SE. Progression model for pancreatic cancer. Clin Cancer Res 6(8):2969 –
2972, 2000. PMID: 10955772.
4 Jones S, Zhang X, Parsons DW, et al. Core signaling pathways in hum an pancreatic cancers revealed by global
genomic analyses. Science 321(5897):1801 -1806, 2008. PMID: 18772397.
5 Winter JM, Yeo CJ, Brody JR. Diagnostic, prognostic, and predictive biomarkers in pancreatic cancer. J Surg Oncol
107(1):15 -22, 2013. PMID: 2272 9569.
6 Donahue TR, Reber HA. Surgical management of pancreatic cancer –pancreaticoduodenectomy. Semin Oncol
42(1):98 -109, 2015. PMID: 25726055.

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Chapter 2.
Pancreatic cancer Management

2.1. More information on the cancer of the head of the pancreas
The main type of cancer that affects the pancreas is the ductal adenocarcinoma, which is twice
as frequent in the head of the pancreas as in the body or tail. Tumors in the head might originate
either in the posterior aspect (uncinate process) or in the anterior aspect of the gland. Ductal
adenoc arcinoma shows intrapancreatic, but also early extrapancreatic tumor extension. Within
the pancreas, the tumor infiltrates the acinar tissue and may extend along the large ducts.
Lymphogenic spread especially along the retroperitoneal channels usually pre cedes
hematogenous metastasis.
At the time of diagnosis over 85% of tumors have extended beyond the organ (Cubilla et al.,
1978) and perineural invasion within and beyond the gland is present. Lymphatic spread is also
found in up to 50% of so -called early cancer of the pancreas with the presence of metastases to
adjacent or distant lymphnodes (Birk et al., 1998b; Satake et al., 1992; Nagakawa et al., 1991)7.
Historically, pancreatic tumors were considered either resectable or unresectable. Th e first
published definition for borderline resectable pancreatic ductal adenocarcinoma (PDAC), which
refers to tumors that are involved with nearby structures so as to be neither clearly resectable nor
clearly unresectable, was by the National Comprehensi ve Cancer Network (NCCN) in 2014.
Aggressive management of this group of patients with neoadjuvant chemotherapy has made
surgery feasible and extended surgical approaches in PDAC have become commonly performed,
which include vascular as well as multiviscer al resections.
The most common site of extralymphatic involvement are the liver and the peritoneum, the
lung is the most frequently affected extraabdominal organ. In the absence of metastatic disease
which precludes resection, assessment of vascular invasion is an important parameter for
determining resectability for pancreatic cancer. From the point of view of arterial vessels, a
tumoral infiltration of a large trunk (celiac axis, superior mesenteric artery, or hepatic artery) must
be carefully anal yzed because it constitutes a contraindication to surgery. However, isolated
involvement of smaller branches such as the gastro -duodenal artery will not preclude surgical
resection. The superior mesenteric vessels are the most frequently involved vessels i n this
cancer, due to their intimate relationship with the head, the uncinate process, and body of the
pancreas. Recent studies have shown that patients with vascular tumor invasion, who undergo
concurrent vascular resection, can achieve long -term survival rates equivalent to those without
vascular involvement requiring pancreatoduodenectomy (PD) alone.
There is now emerging evidence that a subset of patients, categorized as borderline
resectable (BR), may benefit from vascular resection after neoad juvant therapy due to the

7 Birk D, Beger HG. Pancreatic cancer. Nih.gov. https://www.ncbi.nlm.nih.gov/books/NBK6961/. Published 2015.
Accessed May 23, 2019.

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theoretical benefits of downstaging the tumor, treating subclinical micrometastatic disease,
increasing the proportion of patients who will receive and complete therapy, and the ability to
better monitor the tumor’s response to th erapy8.
However, there have also been studies that reports that compared to a standard
pancreaticoduodenectomy, pancreaticoduodenectomy with vein resection was associated with a
greater risk of some specific complications and increase the mortality rate, total hospital stay time,
combine with vein resection have a lower R0 resection rate. Therefore, combine with vascular
resection for pancreatic cancer needs to be carefully selected by the surgeon9.

2.2. Current management of Pancreatic cancer
Over the past 15 years, there have been two different staging systems for pancreatic cancer
patients.
The general guidelines of the Japanese Pancreas Society (Japan Pancreas Society, 1996)
apply to Japanese clients. Western patients are staged in ac cordance with UICC regulations. Both
systems have their strengths and weaknesses. The Japanese system is very accurate in
identifying local tumor development and involving different neighboring pancreatic structures.
Applying JPS staging in patients with p ancreatic cancer requires a very complex resected
specimen pathological work -up. The Japanese system is therefore likely more precise, but more
complex to use as well.
Apart from tumor size and location several other factors are recorded. For serosa l,
retroperitoneal, nerve -plexus, duodenal, venous and arterial involvement separate classifications
are provided. Also, seventeen different lymph node stations are defined with several underclasses
adding up to 34 individual lymph nodes sites. All these c haracteristics are documented
individually. Due to this reason, it has probably not been applied in Western countries.
Much in contrast, the system proposed by UICC (International Union Against Cancer, 1997)
is quite simple to apply but is less pre cise in describing the characteristics of the local tumor
growth than the Japanese system. The UICC system considers lymphnode metastases as the
most important factor, next to the tumor size. The extent of lymphatic involvement is basically
classified eith er as node positive (N1) or node negative (N0) with the minor discrimination
between N1a and N1b signifying one, or more than one, involved lymph node.
Regardless, of which system is applied, surgical resection of the pancreatic tumor is the only
choice for a positive patient outcome. Distant metastases of a pancreatic ductal adenocarcinoma
and gross tumor invasion into the mesenteric root, demanding arterial and venous vessel

8 Goel N, D’Souza JW, Ruth KJ, et al. The Utility of Preoperative Vascular Grading in Patients Undergoing Surgery
First for Pancreatic Cancer: Does Radiologic Arterial or Venous Involvement Predict Pathologic Margin Status?
Journal of Oncology. 2018;2018:1 -8. doi:10.1155/2018/7675262
9 Peng C, Zhou D, Meng L, et al. The value of combined vein resection in pancreaticoduodenectomy for pancreatic
head carcinoma: a meta -analysis. BMC Surgery. 2019;19(1). doi:10.1186/s12893 -019-0540 -6

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resection are contraindications. Despite aforementioned contraindications though, the vast
majority of patients opts for the surgery. Biliary or duodenal obstruction in the present of distant
metastases demand a gastric or biliary bypass. These bypass procedures carry an acceptable
operative mortality of less than 5% and, theref ore, should be favored in patients with a life
expectancy of less than 6 months.
The presence of regional lymph node metastasis is not considered as a contradiction against
resection.
Concerning the surgical approach of pancreatic head carcin oma, depending upon staging ,
the following procedures are used:
 Whipple procedure (pancreatoduodenectomy) : A surgical pr ocedure in which the head of
the pancreas , the gallbladder , part of the stomach , part of the small intestine , and the bile
duct are removed. Enough of the pancreas is left to produce digestive juices and insulin .
 Total pancreatectomy : This operation removes the whole pancreas, part of the stomach,
part of the small intestine, the common bile duct , the gallbladder, the spleen , and
nearby lymph nodes .

 Distal pancreatectomy : Surgery to remove the body and the tail of the pancreas. The
spleen may also be removed if cancer has spread to the spleen. This procedure will not
be discussed since the current thesis focuses in pancreatic head carcinoma.
If the cancer has spread and cannot be removed, the following types of palliative surgery may be
done to relieve symptoms and improve quality of life :
 Biliary bypass : If cancer is blocking the bile duct and bile is building up in the gallbladder,
a biliary bypass may be done. During this operation, the doctor will cut the gallbladder or
bile duct in the area before the blockage and sew it to the small intestine to create a new
pathway around the blocked area.
 Endoscopic stent placement: If the tumor is blocking the bile duct, surgery may be done
to put in a stent (a thin tube) to drain bile that has built up in the area. The doctor may
place the stent through a catheter that drains the bile into a bag on the outside of the body
or the stent may go around the blocked area and drain the bile into the small intestine.
 Gastric bypass: If the tumor is blocking the flow of food from the stomach, the stomach
may be sewn directly to the small intestine so the patient can continue to eat normally.

Except for the surgical procedures, the other most frequently used therapies when dealing with
pancreatic cancer are:
Radiation therapy
Radiation therapy is a treatment for cancer that utilizes high -energy x -rays or other kinds of
radiation to kill or prevent the growth of cancer cells. There are two kinds of radiat ion treatment:

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External radiation therapy uses a device to send radiation to the cancer outside of the body.
Internal ra diation therapy uses a radioactive substance sealed in needles, seeds , wires, or
catheters that are placed directly into or near the cancer. The way the radiation therapy is given
depends on the type and stage of the cancer being treated. External radiation therapy is used to
treat pancreatic cancer.
Chemotherapy
Chemotherapy is a therapy for cancer that utilizes drugs to prevent cancer cells from growing,
either by killing cells or by preventing them from splitting. The medications enter the bloodstream
when chemotherapy is taken by mouth or injected into a vein or muscle and can reach cancer
cells throug hout the body (systemic chemotherapy). The drugs primarily influence cancer cells in
those regions (regional chemotherapy) when chemotherapy is put straight into the cerebrospinal
fluid, an organ, or a body cavity such as the abdomen. Combination chemother apy is an
anticancer drug therapy. The manner in which chemotherapy is administered relies on the cancer
type and phase being handled.
Chemoradiation therapy
Chemoradiation therapy combines chemotherapy and radiation therapy to increase th e effects of
both.
It should be mentioned that p atients with pancreatic cancer have special nutritional needs , which
affects postoperative results. Surgery to remove the pancreas may affect its ability to
make pancreatic enzymes that help to digest food. As a result, patients may have problems
digesting food and absorbing nutrients into the body. To prevent malnutrition , medications that
replace these enzymes must be prescribed .

Chapter 3
Concurrent studies on the subject at hand

3.1. Evaluation of current studies concerning pancreatic head resection