University of Medicine and Pharmacy “Iuliu Hatie-ganu“ Cluj- Napoca Faculty of Medicine License Thesis Upper vs Lower Rectal Cancer: A comparison… [625437]

University of Medicine and Pharmacy “Iuliu Hatie-ganu“ Cluj- Napoca Faculty of Medicine License Thesis Upper vs Lower Rectal Cancer: 
A comparison between mortality, morbidity and surgical approach Coordinator: Sef Lucrari Dr Doru MunteanuGraduate: Antonius Thomas Maria Korschinsky2019

TABLE OF CONTENTS Theoretical Part 1.Introduction 5 ……………………………………………………………………………………….2.Anatomy of the rectum 6 ……………………………………………………………………….2.1.Relations 7 ………………………………………………………………………………………2.2.Blood Supply of the rectum 8 ……………………………………………………………..2.3.Lymphatic drainage of the rectum 9 …………………………………………………….2.4.Nervous Supply of the rectum 9 ………………………………………………………….3.Cancer of the rectum 11 …………………………………………………………………………3.1.Epidemiology 11 ……………………………………………………………………………….3.2.Etiology and Risk factors 12 ……………………………………………………………….3.3.Types of tumors 15 ……………………………………………………………………………3.4.Pathophysiology 16 …………………………………………………………………………..3.5.Clinical presentation 17 ……………………………………………………………………..3.6.Diagnosis 17 …………………………………………………………………………………….3.7.Staging 19 ……………………………………………………………………………………….3.8.Screening 22 ……………………………………………………………………………………4.Treatment 23 …………………………………………………………………………………………4.1.Radiotherapy 24 ………………………………………………………………………………. !2

4.2.Chemotherapy 25 ……………………………………………………………………………..4.3.Biological therapy 26 …………………………………………………………………………4.4.Surgery 26 ……………………………………………………………………………………….4.4.1.Approaches 28 ………………………………………………………………………………4.4.2.Guidelines 31 ………………………………………………………………………………..4.5.Follow up 33 …………………………………………………………………………………….5.Outcome of the treatment 34 ………………………………………………………………….5.1.Success of the surgery 34 ………………………………………………………………….5.2.Complications related to the surgery 34 ……………………………………………….5.3.Post surgical mortality 35 …………………………………………………………………..Practical part 1.Approach considerations 38 ………………………………………………………………….2.Materials and methods 40 ……………………………………………………………………..3.Results 43 …………………………………………………………………………………………….3.1.Patients 43 ………………………………………………………………………………………3.2.Lower rectal Cancer 48 ……………………………………………………………………..3.3.Middle rectal cancer 51 ……………………………………………………………………..3.4.Upper rectal cancer 54 ………………………………………………………………………4.Discussion 57 ……………………………………………………………………………………….5.Conclusion 61 ……………………………………………………………………………………….Bibliography 63………………………………………………………………………………………..
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THEORETICAL PART

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1.INTRODUCTION Rectal cancer means the abnormal and unregulated growth of a tumor on the inner lining of the rectal mucosa. The unregulated growth is done by malignant cells, which underwent modifications causing them to loose the physiological inhibition of growth and division. During the evolution of the cancer the mali-gnant cells can invade the normal tissue and spread via the lymphatics or the bloodstream to other tissues and organs. Rectal cancer is the third most commonly diagnosed cancer in both males and females and it ranks on the second position in the most deadly cancers. With the end of the industrial revolution rectal cancer became a more prominent and important problem for the society with a high rise in incidence in all industrialized countries, this changed in the 1970s from when the incidence of rectal cancer started to decrease, with the decline going on until today. There are different ways of treating rectal cancer: chemotherapy, radiotherapy and surgery. The main surgical approaches are represented by an open ap-proach, laparotomy, and by the keyhole surgery, laparoscopy. As in every surge-ry there are certain complications that can appear hence causing morbidity and mortality. Morbidity being defined as as the occurrence of a medical problem due to treatment and mortality meaning the occurrence of death within 30 days of surgery.
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2.ANATOMY OF THE RECTUM The rectum is the last part of the large bowel, it is continuing the Sigmoid Colon , distinguishable by the fusion of the three Taenia Coli to one longitudinal smooth muscle layer, and it is continuous with the Anal Canal distally. 2The junction with sigmoid colon is found approximately at S3 and the lower end is antero- inferior to the tip of the coccyx, where the rectum passes through the pelvic floor. 3On the internal surface of the rectum 3 folds, the Houston valves, are found. Those internal folds correspond to the external curvatures of the rectum. There are two curvatures on the left of the rectum and one on the right side. The two curvatures on the left are found superiorly and inferiorly, while the biggest cur-vature is located in the middle part of the rectum and is directed towards the right side. 4The rectum measures approximately 15 cm in length and is divided into three parts. The three parts are divided according to their distance from the anal ver-ge: the lower rectum is defined as being 0- 6 cm , the middle part 7- 11 cm and the upper rectum measuring 12- 15 cm from the anal verge. 5It is partially covered in Peritoneum: The upper mobile third is covered anteriorly and laterally by peritoneum, the middle third is only covered anteriorly and the lower third, lying within the muscular pelvis, is not covered at all. Due to the lack of a mesentery the posterior aspect of the rectum is not covered by peritoneum at all. 6
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2.1. RELATIONS The rectum has multiple anatomic relations. The posterior and lateral ones are the same in male and female, only the anterior ones differ according to the gen-der specific anatomy. Posteriorly the rectum is in neighbourhood to the lower half of the sacrum and the coccyx with the presacral space, containing the sacral vessel and the sacral venous plexus, lying in between them. Somewhat more lateral we find the the lumbosacral nerve plexi and the digiformis muscles on both sides. Posterio- in-ferior there is the ano- coccygeal raphe made up of the fusion of the two eleva-tor ani muscles and the the strong recto- sacral fascia. The lateral relations of the rectum are on each side the lateral ligament, consis-ting of pelvic fascia and counting the middle rectal arteries. Another important relation is represented by the inferior hypogastric nerve plexus, which provides sympathetic and parasympathetic innervation to all of the pelvic and perineal organs. In males the rectum is anteriorly related to the urinary bladder, the seminal vesi-cles on both sides, the inferior parts of the urethras with the vas defers crossing them and the posterior surface of the prostate with a rich circulation of small blood vessels around it. The urogenital structures are separated from the rec-tum by the rectovesical fascia aka fascia of Denonvilliers. In females the anterior relations are represented by posterior wall of the vagina, the Douglas pouch and the uterus, with often a part of the ileum lying in bet-ween,. 78
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2.2.BLOOD SUPPLY OF THE REC-TUM The blood supply to the rectum is maintained by the superior, middle and inferior arteries. The superior rectal arteries are continuing the inferior mesenteric artery inferior to the pelvic brim. They travel in the upper mesorectum before dividing into terminal branches supplying the upper third of the rectum. The middle rectal arteries are branches of the internal iliac arteries. They are supplying the middle third and most of the lower third of the rectum. The inferior rectal arteries are branches of the internal pudendal arteries. They are mostly responsible for the blood supply to the anal canal, but through termi-nal branches they also contribute to the blood supply of the lower third of the rectum. The venous drainage of the rectum is done by three veins the superior, middle and inferior rectal veins. There are two venous plexi within the rectum, one is located deeply inside of the submucosa and the other one is superficial external to the muscular wall of the rectum. The superior rectal vein is draining the supe-rior part of the rectum, it is accompanying the superior rectal artery along its course. It is continuing proximally as the inferior mesenteric vein, which will fi-nally drain into the splenic vein, hence the portal system. The middle rectal vein is draining directly into the inferior vena cava, while the inferior rectal vein drains first into the pudendal vein, which will drain into the internal iliac vein and subsequentially into the inferior vena cava as well,,. 91011Due to this complex system of venous drainage the rectum is an important area of anastomosis between the portal and systemic venous system. There are stu-dies highlighting a difference in the metastatic spread in rectal cancer according to the location within the rectum. The possibility of metastases in the lung is hig-her for patients with the primary tumor located in the middle and lower third of !8

the rectum. The causes for this could be that the blood from these areas is drai-ned into the caval system does not pass through the liver first,. 12132.3.LYMPHATIC DRAINAGE OF THE RECTUM The lymphatic drainage of the rectum reassembles the rest of the colon. The rectal lymph is received by the lymphoid follicles located within the mucosa of the rectum. From there the lymph reaches the mesorectal lymphnodes, which are important for the staging of rectal cancer. The mesolectal in proximity to the rectum are the N1 nodes and the more distant, but still inside the mesorectum, nodes are called N2. The principal lymph node for the drainage of the rectum depends on from which area of the rectum the lymph is drained. The inferior mesenteric lymph node is the principal node for the upper and middle third of the rectum and and in parts from the lower portions, too. The lower rectum drains also into the internal iliac lymph node bilaterally. 142.4.NERVOUS SUPPLY OF THE REC-TUM The nervous supply of the rectum is by the inferior hypogastric nerves, which are the nervous supply to the whole pelvic cavity. They travel on the lateral sides along the rectum. These nerves are the continuation from the superior hypo-gastric nervous plexus. For the sympathetic and parasympathetic innervation the inferior hypogastric nerves receive also branches from the sacral and pelvic splanchnic nerves. The inferior hypogastric nerves give of numerous branches including the middle rectal plexus, the vesicle plexus, prostatic and uretero- va-ginal plexus, which travel alongside the arteries supplying the territories. The nerve supplying the lower part of the rectum below the pectinate line and the external anal sphincter is the inferior rectal nerve. It has its origin either from the pudendal nerves or from the sacral plexus. Its course is together with the inferior hemorrhoidal vessels through the ischio- rectal fossa. 15 !9

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3.CANCER OF THE REC-TUM 3.1. EPIDEMIOLOGY Colorectal cancer is the third most diagnosed malignancy world wide in 2018 1.850.000, which correlates to 10% of all cancers, only lung and breast cancer being diagnosed more frequently and in the newest studies from 2018 colorectal carcinoma is carrying the second highest mortality with 881.000, which is around 9% between all the death related to cancer, with again only lung cancer being more deadly. In males colorectal cancer is with the third highest inci16-dence and the fourth highest mortality among all malignancies, while in females it takes rank 2 in incidence and rank 4 in mortality in comparison to other neo-plasms. 17 In the European Union the statistics for 2017 say that the incidence for rectal cancer is 15- 25/ 100.000 population per year with a mortality of approximately 4- 10/100.000 population per year. Median age is around 70 years at diagno-sis. 18The burden of CRC varies widely in a global picture, like its advent after the end of the industrial revolution suggested CRC is a problem of the developed world. Nearly two thirds of CRC cases come out of countries with high or very high HDI, human development index. In a trend we see rising incidence in countries of eastern Europe, Asia and south America. According to demographic projec-tions the incidence of CRC is said to rise to 2.200.000 by 2030. On the other hand side there is also a positive development going on, because in the coun-tries with the highest HDI- USA, New Zealand, Australia, Western Europe inci-dence and mortality of CRC is either stabilising or even declining. The decrea-sed mortality and improved survival in the countries of higher HDI is linked to !11

adoption of best practices in cancer treatment and management. This includes early polyp removal and early detection of neoplasms by nationwide screening programs and colonoscopies. Since the introduction of the screening programs in the 1990s in the USA the incidence firs increased but by now we find decli-ning numbers in mortality and even in incidence in those countries. 193.2.ETIOLOGY AND RISK FACTORS A true etiology for rectal carcinoma is not known. It is an acting together of diffe-rent risk factors and personal predispositions that cause the formation of a neo-plasm. There is evidence that etiologies and risk factor for rectal carcinoma dif-fer from the ones for CRC. We can divide the risk factors in changeable and non changeable risk factors. 20The changeable risk factors are mainly environmental risk factors. These risk factors come mainly with living in an industrialized country and are like a charac-terization of the modern average human being. 21A diet high in red and processed meat, high in fats and calories and low in fibers is proven for increasing the risk of rectal cancer. The combination of an high amount of fats and a low amount of fibers is generating a toxic environment of the rectal mucosa, causing injuries to it and taking part in the carcinogenesis. This process is hypothesized to be caused by a reaction of the dietary fats with the bacteria of the colon and the increased formation of bile, which in turn also reacts with the anaerobic bacteria of the colon.In this aspect also nitrates and nitrites, which are used in processed meat as preservatives, are thought to pose a risk for the development of cancer. This typical western diet is often also ac-companied by obesity and physical inactivity, which are also acknowledged to increase the risk for developing cancer. The cause is thought to be increased levels of circulating insulin, which produces an increase in colon cell production and down regulates apoptosis. This makes is understandable that by now Dia-betes type 2 is also considered a risk factor for CRC, even though the real rela- !12

tion is hard to establish due to the numerous accompanying risk factor coming with diabetes. 22There are studies correlating Human Papillomavirus positivity and an increased prevalence of CRC cases, this would mean that there is another pathway of carcinogenesis for CRC. This risk factor needs to be investigated closer. 23There are also diets, which are protective factors. Those should be higher in fruits and vegetables, containing natural antioxidants, carotenoids and phenols. Furthermore the use of fish and olive oil and supplements like vitamin D and fo-late was also shown to be beneficial. Additional habitual physical exercise was also proven to be a protective factor. The often talked about chemoprophylaxis with Aspirin was proven to be true in patients with Lynch syndrome , but it works rather on the right side of the colon in preventing carcinogenesis and in healthy individuals a real conclusion in the protectiveness could not be drawn yet. Bi-phosphonates are also reported to have a statically significant reduction in CRC. 24Tobacco and heavy alcohol is a risk factor for a lot of cancers, one of those being rectal cancer. Both being known carcinogens. Research shows that as many as 4 drinks per week increase the risk to develop cancer by 52%. The mechanism behind the carcinogenicity is believed to be due to decreased folate synthesis because of the alcohol intake. 25Factors that cannot be changed by the patient are age, race, personal or family history of a CRC, genetic predisposition due to a history of inflammatory bowel syndrome or a genetic syndrome. The mean age at diagnosis is 70 years in Europe and the prognosis is that in the future the age will even rise more. 90% of diagnoses are made after the age of 50 years old, but nonetheless there are also cases in younger populations and the incidence in younger people is rather increasing. So any kind of com-plaints leading to the a possible neoplasm in the rectum need to be taken se-rious also in young individuals. !13

Studies in the US showed that African Americans have the highest percentage of incidence and mortality among all the races in the US. The Ashkenazi Jews have one of the highest incidences of all ethnic groups world wide. 26A patient with a history of adenomatous polyps, which are in the vast majority the direct precursor of rectal cancer, is understandably at a higher risk for deve-loping a rectal carcinoma. Furthermore patients with a history of CRC are at a higher risk to develop a new cancer in a new or the same location in the colon and rectum, even if they were healed at one point. The risk is also here higher if the patient was younger than 45 years at the time of the first diagnosis. In plus there are studies, which show an increased incidence for CRC if the patient had gynecological cancers like ovarian or uterine cancer before. There is also evi-dence that patients with acromegaly are at increased risk for developing CRC, due to their increased levels of circulating human growth hormone. Also there are studies correlating cholecystectomy to an increased risk to develop CRC , due to the constant exposure to bile acids in the GI tract, which causes in time causes a build up of carcinogenic bile acid byproducts,. 2728The risk for developing CRC is increased in people, who have a positive family history in first degree relatives. This risk increases even more if the diagnosed relative was younger than 45 at the time of diagnoses or if there are more than 1 relative affected. There is even evidence that persons are at increased risk if there first degree relatives with a history of adenomatous polyps in the family. The correct relationship between the family history and the development of can-cer is not fully understood but it seems to be a working together of genetic pre-disposition and often similar environmental factors . 29Patients with ulcerative colitis and Crohn’s disease are at increased risk for de-veloping rectal carcinoma, especially if the rectum is primarily involved. The chronic inflammation of the rectal mucosa is responsible for dysplasia of the mucosa, which is a precancerous lesion and can develop into a tumor. 30Inherited polyposis syndromes account for around 5% of CRC. In these patients a clear cut genetic etiology for the cancer can be established. !14

Familial adenomatous polyposis is an autosomal dominate gene defect of the APC gene on chromosome 5. The risk for developing a colorectal carcinoma at the age of 50 years old reaches 100%, while the mean age at diagnosis is 39. The disease is characterized by hundreds to thousands of colorectal and duo-denal adenomatous polyps. There is a milder form called attenuated familial adenomatous polyposis, which also has a gene defect in the APC germline, but it has less polyps and those are mainly located in the right colon. 3132Lynch Syndrome, also called hereditary non- polyposis colon cancer, is affecting 1: 5000 people and is reported to cause between 3- 10% of CRC. The etiology of the Lynch Syndrome is found to be a mutation of one of the DNA mismatch repair genes. The inheritance is autosomal dominant. The lifetime risk is 70- 80% and the tumors have a predisposition to develop in the right colon. Patients with Lynch syndrome are at increased risk to develop other type of cancers as well such as stomach, small intestine, hepatobiliary, bladder, skin and brain cancer. 33There are also other inherited syndromes, which carry an increased risk, but those are mainly affecting the proximal colon so they are spared in this review. 3.3. TYPES OF TUMORS Over 90% of all rectal cancers are adenocarcinomas, originating from the epit-helial mucosa of the rectum. The adenocarcinomas are subdivided into different types, including mucinous, Signet ring, medullary and serrated carcinomas. The rest are rare types and is made up of neuroendocrine tumors, squamous cell carcinoma, adenosquamous carcinoma, spindle cell and undifferentiated carci-nomas, mesenchymal tumors and lymphomas. 34In the pathology the grading according to the grade of differentiation of the tu-mor needs to be done, giving clues about the prognosis. Another important as-pect is the level of infiltration, differentiating between invasive and expansive growth pattern.Other features to be determined by the pathologist are fibrous !15

lesions around the tumor, necrotic lesions within the tumor and of course the lsesions according to the TNM system. 353.4. PATHOPHYSIOLOGY Carcinogenesis is the stepwise mutation from a physiological normal cell to a malignant cell. Carcinogenesis has three steps: initiation, promotion and pro-gression. It is due to genetic mutations and epigenetic aggressions, which result in the activation of oncogenes and in the inactivation of tumor suppressors. 36For the carcinogenesis there have been three different pathways discovered. Those three either are alone responsible for the malignant mutations or are ac-ting together in the development of the carcinoma. The pathways are firstly the chromosomal instability (CIN), secondly CpG island methylator phenotype (CIMP) and thirdly microsatellite instability (MIS). The carcinogenesis according to the genetic mutations shows importance difference compared to the one of Colon carcinomas, implying that the not just the location is different between the rectal and colon cancer. CIN is the most common pathway among the three. It is characterized buy a mutation in the APC gene, which is then followed by a mutation in the the onco-gene KRAS causing its activation and in the inactivation of the tumor suppressor gene TP53. In tumors caused by the CIN pathway we will find cells with an ab-normal number of chromosomes and loss of heterozygosity. If the defect in the APC gene is inherited we talk about familial adenomatous polyposis syndrome. The characteristics of the CIMP pathway are the promoter hypermethylation of tumor suppressor genes. It is often accompanied by BRAF mutations and micro satellite instability. The hallmark of the MIS pathway is the inactivation of DNA repair genes, which are responsible to repair DNA mismatches. The MIS is found in patients with Lynch syndrome, but also in patients who have sporadic neoplasia in the rec-tum. 37 !16

The majority of rectal carcinomas, 35%, are considered to be sporadic. Out of all types of carcinomas adenocarcinomas are with 98% the most frequent ones. In adenomacarciomas there is a multistep sequence leading from the normal proliferation of the rectal mucosa to the final development of a tumor. It usually starts with the dysplasia of crypt, which will grow and form new crypts, which then together will be forming adenomas. These adenomas will change the and further increase in size and due to gene mutations will form a carcinoma at the end of the sequence. The change from an adenoma to a carcinoma is approxi-mate to take 10 years. 383.5. CLINICAL PRESENTATION The clinical presentation of patients with rectal cancer is mostly unspecific and a lot of patients are diagnosed during routine examinations and screenings. It is very important to take a careful history and physical examination of the patient complaining of signs and symptoms, which can be attributed to rectal cancer and to follow up on these with paraclinical examinations. 39The signs and symptoms of patients include fresh blood on stool, which a lot of patients mistakenly take as a sign for hemorrhoids. Others complain of tenes-mus, increased urgency to defecate and a constant feeling of having to defeca-te. A change in bowel habits ranging from very thin, pencil like stools due fecal incontinence is found in a lot of patients. This change in bowel habits might also just present itself as bloating, cramps or diffuse abdominal and pelvic pain. More unspecific signs are weight loss, fatigue and malaise. There are also a minority of patients with rectal cancer, whose first presentation to the doctor will be an emergency, as a stenosis caused by the tumor, peritonitis or a GI tract blee-ding, . 40413.6. DIAGNOSIS !17

During the process of diagnosing rectal cancer a thorough history is vital. The aforementioned risk factors need to be evaluated, a possible personal history of IBD or other gastrointestinal diseases with the according treatment and a family history concerning rectal cancer needs to be done. The physical examination has to include the digital rectal examination for palpa-tion and description of the tumor. Furthermore the physician has to check for lymphadenopathy and possible hepatomegaly. The physical exam should be followed by a lab exam. In the lab exam a CBC should be taken to evaluate a possible anemia. In the cancer patient one would expect to have an iron deficiency anemia, hence a microcytic, hypochromic an-emia. Out of the serum we can also take antigen assay of carcinoembryonic CEA and cancer CA 19-9. Those levels cannot be used alone for diagnosis but are also valuable for monitoring of the disease, giving clues about possible reoccurrence and also in the height of the titre about metastatic disease. 42A colonoscopy with the extraction of biopsies and followed pathological exami-nation has to be done, which is compulsory for the right staging of the disease. During colonoscopy the tumor itself can be visualized and evaluation of type of tumor and the way of growth and other aspects of the tumor itself are readily available. In plus possible simultaneous neoplasms of other parts of the GI tract can be found. The pathology will decide what kind of tumor it is and if there are genetic mutations giving hints about which carcinogenesis pathway caused the neoplasia. Other possibilities for a visualization of the GI tract include flexible sigmoidoscopy, CT, MRI and Barium enema radiography. 43After the initial diagnosis of rectal cancer the staging of the cancer needs to be done, including the local extent of the tumor, the spread of the tumor into lymph nodes and in the form of metastases into other organs and the pathology of the tumor. The staging is done nowadays mostly according to the TNM system. His-torically Duke’s system, which was then adapted by Astler and Coller, has also some value. A MRI or an intrarectal ultrasound to evaluate the spread and inva-sion of the tumor into the rectal wall, adjacent structures and local lymphadeno- !18

pathy is performed. The aim is to establish the size of the tumor and the depth of its invasion in relation to the mesolectal fascia. Furthermore it will establish if safe surgical margins can be achieved or if there is the need to downsize the tumor before performing surgery. For metastatic evaluation a CT of the thorax, abdomen and pelvis is done. Other important factors for the staging, which are not yet introduced into the classical staging categories is the pathological sta-ging, which should include the CEA titre before the treatment, lymphovascular and perineurial invasion, MSI, mutation of KRAS, NRAS and BRAF and the tu-mor regression score during treatment. Those have prognostic and predictive importance and also implications on which treatment will be the most effective. The molecular characteristics of the cancer have a broad range and are divided into genetic and epigenetic alterations, mutations of specific genes, levels of gene expression and genetic polymorphism. The determination of all those will provide the best possible care of patients in treatment for rectal carcinoma. 443.7. STAGING Duke’s classification was adapted by Astler and Coller and these added subca-tegories to be able to have a more specific classification. Stage A: Limited to mucosa Stage B1: Extending into muscularis propria but not penetrating through it- Lymph nodes not involved Stage B2: Penetrating through muscularis propria- Lymph nodes not involved Stage C1: Extending into muscularis propria but not penetrating through it- Lymph nodes involved Stage C2: Penetrating through muscularis propria- Lymph nodes involved Stage D: Distant metastatic spread !19

The TNM staging system is the by now most used one. It was established by the American Joint Committee on Cancer. Primary tumor (T) includes the following: TX – Primary tumor cannot be assessed or depth of penetration not specified T0 – No evidence of primary tumor Tis – Carcinoma in situ (mucosal); intraepithelial or invasion of the lamina propria T1 – Tumor invades submucosa T2 – Tumor invades muscularis propria T3 – Tumor invades through the muscularis propria into the subserosa or into non-peritonealized pericolic or perirectal tissue T4 – Tumor directly invades other organs or structures and/or perforates the vis-ceral peritoneum Regional lymph nodes (N) include the following: NX – Regional lymph nodes cannot be assessed N0 – No regional lymph node metastasis N1 – Metastasis in 1-3 pericolic or perirectal lymph nodes N2 – Metastasis in 4 or more pericolic or perirectal lymph nodes !20

N3 – Metastasis in any lymph node along the course of a named vascular trunk Distant metastasis (M) include the following: MX – Presence of metastasis cannot be assessed M0 – No distant metastasis M1 – Distant metastasis According to the TNM staging we can classify the different rectal cancer stages into I- IV. The 5 year survival is predicted according to the cancer stages. Stage I: T1-2 N0 M0- 5 year survival: > 90% Stage II A: T3 N0 M0- 5 year survival: 60- 85% Stage II B: T4 N0 M0- 5 year survival: 60- 85% Stage III A: T1- 2 N1 M0- 5 year survival: 55- 66% Stage III B: T3- 4 N1 M0- 5 year survival: 35- 42% Stag III C: T1- 4 N2 M0- 5 year survival: 25- 27% Stage IV: T1- 4 N0-2 M1- 5 year survival: 5- 7% Other factors influencing the prognosis for rectal cancer patients and the rate of reoccurrence after surgery are: the quality of the surgeon to obtain clear mar-gins,the grade and stage of the primary tumor and the location of the tumor, the-re is evidence that lower rectal carcinomas have a higher rate of reoccurrence than the others. Altogether with the individual factors of the patient determining the survival. 45 !21

3.8. SCREENING Screening is a measure to prevent the occurrence of rectal cancer or to be able to treat the cancer in early stages. It is fundamental in the fight against cancer. There are different guidelines according to countries. Screening should be star-ted at 45 years of age, according to the American Cancer Society. There are multiple types of tests that can be done. We divide those into stool based tests and imaging examinations. The stool based tests are the following: Guiac based fecal occult blood test is a coated, which in contact with blood within the feces changes colour. It is usually taken home by the patient and then interpreted by the general practitioner. The blood could be originating from carcinomas or adenomas. This screening has shown to be very effective lowering the mortality with 33% and the occurrence of metastases with 50%. If the FOBT is positive it should be followed by a co-lonoscopy. This test should be done very year. Another option is the Fecal im-munochemical test, which also is used to detect occult blood within the stool. In the FIT antibodies are used to determine if there is blood or not in the stool. The FIT is very specific for bleeding of the lower GI tract as it is detecting globing molecules, which would be metabolized if they were originating from a bleeding in the upper GI tract. As the FOBT it should be done annually. The third stool based test is FIT DNA test, which is detecting altered DNA in the stool. Accor-ding to the ACS this should be done once every three years. 46Imaging examinations include: flexible sigmoidoscopy for the visualization of the rectum and distal part of the colon. It is a more comfortable technique for the examination of the distal GI tract, as the patient only needs an Enema and not a whole bowel cleanse and there is also no sedation needed. Despite this the fle-xible sigmoidoscopy is a very effective screening method studies show that it decreases the incidence of cancer with 50% and the mortality with even 60- 70%. Plus there is the possibility to treat and excise possible polyps immediately while performing the procedure. The guidelines recommend to do this examina-tion every five years. Colonoscopy is for the examination of the rectum and the !22

whole colon. It is the gold standard for screening and it gives the practitioner the best possible visualization and also the ability to perform polypectomies, biop-sies, hemostasis in case of bleeding, but the patient needs to have a complete bowel cleanse and it is preferred if the patient is sedated during the treatment. This should be done once every ten years. The last option is CT Colonography, which is imagining the GI tract with X- Rays. It is done in patient, who are not well fit for a colonoscopy or who prefer to avoid the discomfort. After filling the GI tract with air a CT is performed. It has a good sensitivity for larger polyps but it has its limitations due to false positive results and the inability to detect flat polyps. Also this should be done every five years. The guidelines also provide information for patients, who are at increased risk for developing rectal cancer. Risk factors were described earlier and include: Family history of CRC or polyps, family history of FAP or HNPCC, personal his-tory of CRC, personal history of IBD. Patients with these conditions should start the screening at an earlier age and should perform colonoscopies more fre-quently than the 10 year interval. 474.TREATMENT The treatment of rectal cancer is, as in every other neoplastic disease, multidi-sciplinary. The treatment options are depending on the TNM staging of the di-sease, the size and location of the tumor and also on individual factors of the patient. According to the NCCN guidelines generally the primary treatment for !23

cancer with T1-2 N0 M0 is surgical excision of the tumor. Every cancer staged higher than this need neoadjuvant treatment, followed by a restaging, surgery and adjuvant therapy. In the last years different randomized trials showed the 48improvement of treatment outcome with the improvement of staging and the multimodal approach, with the local failure rates at less than 10%. Especially higher stages of cancer profit from preoperative treatment, which fa-cilitates down staging with increased respectability, higher probability to obtain clear CRM and sphincter preservation. Furthermore it lessens the risk of toxicity and risk for metastasis. The treatment of cancers of the lower rectum is especially difficult due to the closeness to the anal sphincter, which makes it hard to achieve CRM and the preservation of the anal sphincter. 494.1. RADIOTHERAPY There are three different modes of radiotherapy in the treatment of rectal can-cer: neoadjuvant, adjuvant and palliative radiation therapy. The implication of radiotherapy into the treatment plan of rectal cancer showed important impro-vement in the outcome, but there are also important downsides to it. Preoperative radiation therapy is proven to decrease the risk of local recurrence, other advantages of neoadjuvant radiation therapy is the decreasing of the size and the invasion of the tumor making complete removal possible. In the studies from the Stockholm Rectal Cancer Study Group it showed that the short term radiotherapy with 25 GY in five sessions during one week is superior to 35 GY in five sessions within a week, in both groups the surgery was performed one week after the end of the radiation therapy. In the group treated with 25 GY the survival of the patients was better compared to patients not treated with radio-therapy before surgery. Furthermore the researches found that the treatment with 35 GY does not just not improve survival in patients, but also found a pos-sible link that it increases the postoperative mortality. Indications for preopera50- !24

tive radiotherapy are: fixed tumor, evidence of ureteral obstruction, invasion of adjacent structures, presacral adenopathy, anal canal invasion, uT3 and uT4 and poorly differentiated histology. The downsides of preoperative radiotherapy include: immune dysfunctions causing postoperative morbidity, delayed healing, nervous damage causing anorectal malfunction, also negative effects on male sexual fiction and urinary function have been observed. Also in the Swedish study side effects of GI tract malfunction were reported, namely, incontinence, increased frequency and urgency to defecate, alongside problems in adequate emtptying. Postoperative radiotherapy should be given to patients with high risk of local re-currence of the tumor. Those are patients with poorly differentiated carcinomas, pT3 and pT4 lesions and N positive pathology reports. The treatment should start not earlier than one month after surgery and not later than 2 month after surgery. The total dosage applied to the tumor bed should be approximately 60 GY. There are also numerous possible complications with postoperative radiati-on therapy. The most important among those is the risk of small bowel obstruc-tion. Others include anastomotic strictures, delayed healing, worsening postope-rative fatigue, toxicity, formation of fistulas, mucous discharge, urgency, tenes-mus and bleeding. 514.2. CHEMOTHERAPY The use of chemotherapy in rectal is controversial to this day, but studies show that the concurrent administration of radiation and chemotherapy has more fa-vorable outcomes in terms of overall and disease free survival. Chemotherapy can be also administered as neoadjuvant or adjuvant therapy. 52The benefits and indications for neoadjuvant radiation therapy are described before and those are the same for the neoadjuvant treatment with radiation and chemotherapy combined. It is proven that the combined administration is incre-asing the local response of the tumor, but at the price of increased toxicity. Ano-ther advantage of CRT is that with the the combined therapy also the chances !25

of metastasis are tackled and the appearance of metastasis is the major mode of failure of surgery in rectal cancer. 53Adjuvant chemotherapy is beneficial for patient with pT2 and pT3. The chemo-therapy is largely based on 5- FU. But research shows that the combination of multiple chemotherapeutic agents increases the effectivity of the treatment, but with a substantially increased toxicity. Common combinations are 5- FU with oxaliplatin and leucovorin or with capecitabine or irinotecan. 54Complications of chemotherapy are multiple and according to patient and drug individual. There are multiple side effects of chemotherapy, which include le-thargy, nausea, diarrhea, vomiting, skin erythema or desquamation, hair loss, change of appetite and more importantly bone marrow suppression, nervous damage and liver toxicity. 4.3. BIOLOGICAL THERAPY There is also biological therapy available for rectal cancer, which can be admi-nistered according to the genetic and epigenetic mutations found in the patholo-gy. Usually this kind of therapy is administered in metastatic disease together with CRT and has shown promising results in prolonging survival. It is represen-ted by Cetuximab is an EGFR inhibitor, which should be avoided in patients with KRAS mutation. Pamitumumab, which is an monoclonal antibody for EGFR, is 55very effective in the treatment of KRAS wild type positive rectal cancer. Bevaci-zumab is a monoclonal antibody, which blocks the VEGF- A. 564.4. SURGERY Surgery plays a crucial part in the treatment of rectal cancer. It gives the pati-ents the chance to be healed from the disease. The oncologic surgery should try !26

to achieve 4 major goals, which are excision of the entire tumor, so negative margins, restoration of anatomy, minimization of the functional impairment, as-suring the best quality of life possible. The surgical treatment of rectal cancer goes back to antiquity, but the first successful excision of a tumor of the rectum was performed 1826 in France by Lisfranc. This was the birth of the abdomi-noperineal resection. In 1908 Mile stated that the appropriate treatment of rectal cancer should include vast excision of the lymphnodes. In 1982 the next miles-tone of rectal cancer surgery was set , when Heard et al introduced the TME. The complete mesorectum was en bloc cut out. By this the recurrence rate could be decreased to 3.7% for the 5 years post surgery. Also in the 1980 the Transanal endoscopic microsurgery was developed, which allows excision of polyps, Tis and T1, or surgeries with a palliative intent. The next step was made by Jacobs et al, who introduced laparoscopic surgery to the rectal cancer treat-ment. Even though difficult to perform it shows promising results. Color 2 trial shows nearly equal results between laparoscopic and AR regarding oncologic criteria , with a much better short term morbidity profile. Still there are doubts about an increased number of positive CRM, especially in lower rectal cancer. Given the difficulty to operate in the closed space of the pelvis there is still some room for improvement and the outlook in the potential future standard of rectal cancer surgery was given in 2009 by Lazy et al. Consisting of a transanal TME, supported by surgical roboter, given a better view and possibility of mobilization and TME of lower rectum plus the huge advantage of the possibility to achieve a very low coloanal anastomosis. 57There are different factors influencing the choice of operation and which kind of operation to perform. Multiple studies shows that for a successful surgery the experience of the specialist surgeon, the volume of work and the knowledge concerning the surgical technique is vital. The most important factor for the 58choice of surgery is the level of the tumor from the anal verge. In literature it is said that a tumor seven or less centimeter from the anal verge requires APR, 8 or more centimeter can be done by anterior resection. Also the macroscopic 59appearance of the tumor needs to be taken into account as the margins of re-section are bigger for infiltrative carcinomas. Furthermore the indications for neoadjuvant CRT need to be respected as it is proven that this helps resectabili- !27

ty of the tumor, the patient needs to be able to deal with a surgery in psycholo-gical and general health aspects. Also the smaller pelvis in men needs to be ta-ken into account as the body mass, because in obese patients lower anastomo-sis is harder to achieve. Rectal surgery is very challenging due to the close proximity of the organs and nervous vascular structures in the narrow pelvis. The anatomy was presented at the beginning and the complications appearing due to injury to these structures is also presented below. This difficulty means for the surgeon that it is crucial to respect the planes of dissection during the mesolectal excision. The mesorec-tum with the perirectal fascia around has to stay intact. The excision has to be done in the avascular plane between the perirectal fascia and the visceral pelvic fascia, presacral fascia and the Denonvillier’s fascia. 604.4.1. APPROACHES Local excision is done through a transanal approach of the lesion, which limits this approach to tumors of the distal rectum. Allows the resection of lower rectal cancers, which are T1, well differentiated and less than 3 cm lesions. The tu-mors should not involve the muscularis propria. For surgeries with curative in-tent a full thickness excision until the perirectal fat gets visible should be perfor-med. Local excision is an unsatisfying surgical technique as it has a very high rate for local recurrences, which then make either radical surgery or CRT inevi-table. 61Transanal endoscopic microsurgery follows the same principle as the transanal excision but due to the inflation of the GI Tract with CO2 and small instruments the surgery on higher lesions Thant the distal rectum is also possible. Also here a close follow up is necessary as the risk for recurrence is also high. But in both before mentioned the morbidity and mortality is very low compared to the radical excisions. 62 !28

Abdominoperineal resection- in the past the indication for APR was T1 high risk or T2 in the lower rectum. Nowadays APR is used if the tumor is invading the sphincter or a distal negative margin is not achievable. The approach consist of complete resection of anus, rectum and the mesorectum. By this a complete tumor excision with negative margins is achieved, but this technique will leave the patient with a lifelong sigmoidostomy. APR is carrying a high morbidity and a significant decrease in the quality of life in the patient. 63Hartmann’s procedure is the resection of the rectum without a anastomosis, but with an ileo or colostomy. Also here the patients suffer from high morbidity, psy-chological distress and low quality of life. Anterior resection is the most used surgical treatment for rectal cancer. It means the approach through the abdominal cavity to the pelvis with complete TME rec-tal excision. It enables the surgeon to facilitate an anastomosis and continuity of the GI tract. There are high, low and ultra low anterior resection. The latter is possible because of the advent of staplers that allow the formation of an anast-omosis at a level usually not reachable from the the abdominal approach. This is also possible because the minimally accepted distal margin is 1 cm in lower rectal cancer, while the ideal is 2 cm, proximal margins should be more than 5 cm. Here a temporary ileostomy needs to be considered as the anastomosis in the distal rectum has a high risk of leakage. A straight coloanal anastomosis has a risk of stool incontinence. Thats why some surgeons install a so Called J 64Pouch or other kind of pouches to create some kind of reservoir, like the rectum used to be, before the anal canal. By this increasing the life quality of the pati-ents significantly. The coloanal anastomosis needs to be tension free, that why a complete colon mobilization is done before and a good blood supply needs to be present. 65Laparoscopic total mesorectal excision- After the advent of the laparoscopic technique for the cholecystectomy surgeons started to also use this technique for the treat of colon cancers first and then for the treatment of rectal cancers. But the surgery inside of the pelvic area is very difficult due to the limit available space for the surgery. Laparasocopic surgery can be performed on all levels on !29

the rectum. In the hands of an experienced it is safe and the short term outcome is better compared to the laparotomy. Risk factors laparoscopic surgery inclu66-de: visceral injury. Bleeding, intestinal perforation, vascular injury, intraperitoneal adhesions and subcutaneous emphysema. The short term outcome in patients 67treated with laparoscopic surgery are very favorable for the patients, less blood loss, with less pain and need for pain medication, shorter hospital stays and de-creased number of infections and post surgical complications. 68COLOR II trial. It was undertaken in 30 hospitals in 8 countries and 1044 pati-ents were included. Short-term outcomes showed less blood loss, less pain and shorter hospital stay after laparoscopic resection with comparable quality of the resected specimen as in open surgery. Recently, the COLOR II study group pu-blished their long-term outcomes and reported that laparoscopic surgery for rec-tal cancer resulted in similar rates of local recurrence and disease-free and overall survival compared with open surgery. The British Classicc trial also 69compared open with laparoscopic surgery and showed a non significant higher positivity rate of the circumferential resection margin in laparoscopic compared to open surgery. However this did not translate into an increase of cancer recur-rence. The analysis of a lot of trials show that there is no inferitority of the on70-cologic results in laparoscopic surgery with favorable short term results. But due to its difficulty it is really dependent on the expertise and case load of the opera-ting surgeon and the whole surgical team. Another surgical approach recently introduced was the taTME, which stands for transanal total mesorectal excision. It is meant for tumors of the lower and midd-le rectum. Introduced by Lazy et al. it is promising an improved visualization of the surgical field and by this better oncological and functional outcome compa-red to laparoscopic and open TME. There is a COLOR III trial going on to com-pare taTME to the other approaches. The COLOR III is showing promising short term results in terms of CRM and functional outcome of the surgery, but the longterm result of recurrence of local disease need to be waited for to come to the conclusion if taTME should become a surgical standard for middle and lower rectal cancer. 71 !30

4.4.2. GUIDELINES The guidelines of the NCCN state the appropriate treatment for every stage of rectal cancer. Of course one always needs to take into account the general sta-tus and the will of the patient to perform surgery. In plus the location of the tu-mor needs to be appreciated, as an invasion of the sphincter or other change the whole surgical approach and outcome even for small non spread carcino-mas. T1 N0 M0 should be treated with a transanal excision. This should be followed by a pathological exam to prove that it really was just a pT1. If this is proven the further treatment will be just observation, which means proctoscopy every 3- 6 month for the first two years, followed by biannually examination for the next three years. Colonoscopy is performed one year after surgery and if there are no advanced adenomas it will be repeated after three and five years. If there advanced adenomas it will be repeated in one year. For stages T1 N0 M0, which are not appropriate for transanal excision, and for T2 N0 M0 the primary treatment should be trans abdominal resection. If proven that the tumor is only maximum pT2 N0 M0 also here the adjuvant treatment consists only of observation. If the pathology report of the surgical specimen states that the tumor was actually a pT3 the patient will need adjuvant chemo-therapy with radiotherapy, in a careful selected patient group also observation will be sufficient. If we find a pT4 N0 M0 or pT1- 4 N1-2 M0 we will need a regi-men of Chemotherapy, preferably FOLFOX or CAPEOX and radiotherapy. T3 N any M0 with clean circumferential margin and T1-2 N1-2 M0 need to recei-ve neoadjuvant treatment, should then be restaged, with the decision to perform surgery or to get chemotherapy, if surgery is not indicated. For the neoadjuvant therapy there are three options: either combined chemo and radiotherapy or short course radiotherapy alone, after which surgery can be performed. The surgery should be performed either within one week after the radiotherapy or delayed to six to eight weeks after it. The surgery should be followed by adju- !31

vant chemotherapy. The third option is chemotherapy alone, followed by combi-ned chemo and radiotherapy and then restaging and decision for or against sur-gery. If the patient is operated there is no need for an adjuvant chemotherapy. T3 N any M0 with involved CRM T4 N any M0 0r any other locally unresectable or medically inoperable disease has to be treated with neoadjuvant treatment. There are two possibilities chemotherapy together with long term radiotherapy. In this option the patient is restaged six weeks after finishing the radiotherapy if the CRM is clear surgery can be performed, if adequate, and should be followed by adjuvant chemotherapy. If the CRM is not clear or we find a bulky disease the guidelines advise to perform 12- 16 weeks chemotherapy, followed by res-taging. If the surgery is performed the patient will also need here adjuvant the-rapy in form of chemotherapy. The other possibility is to start with 12- 16 weeks of chemotherapy alone followed by chemo and radiotherapy. If surgery is per-formed here we need to observe the patient as explained above. In both possi-bilities if surgery cannot be performed the treatment for the patient will be che-motherapy or chemo and radiotherapy combined according to the individual fea-tures of he patient. In disease with suspected or proven metastasis development it first needs to be decided if the metastases are resectable or not. In case of resettable metastatic disease the patient is treated first with chemotherapy alone, followed by short term radiotherapy and restaging. In a positive evolution the staged or simulta-neous surgery on the metastases and the primary tumor can be performed. If the metastases cannot be excised there can be local measurements, like ablati-on, applied. On the other hand side if there are unresectable metastasis the tre-atment is started with chemotherapy after which the respectability is assessed if there is the possibility to operate on the metastases a short term radiotherapy is performed and the staged or simultaneous surgery on tumor and metastasis. If the metastases are also unresectable after the chemotherapy the progression of the tumor needs to be determined if there is no progression chemotherapy is done plus minus radiotherapy. If there is progression of tumor growth radiothe-rapy before the chemotherapy is recommended. 72 !32

4.5. FOLLOW UP The guidelines of the NCCN have the following content for follow up of patients treated for a stage II and III recta carcinoma: History and physical examination every three to six month for the first two years and biannually for the following three. The same time pattern is done for the CEA titre. A colonoscopy should be done one year, then three years and then five years after the surgery. A chest, abdominal and pelvic CT is meant to be performed annually for five years. 
73
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5.OUTCOME OF THE TREATMENT 5.1. SUCCESS OF THE SURGERY The goal for the treatment of rectal cancer needs to be to optimize disease free and overall survival of the patients, but the CRM is not the only marker for suc-cess: a restored anatomy with minimal functional impairment and maximal quali-ty of life are often just as valuable for the patient. This has to be achieved in a multidisciplinary approach. The only curative method is surgery and for this the excision of the tumor with an intact mesorectum and a CRM is needed. The success of the surgery is supported by adjacent CRT, which improves survival and decreases the risk of local recurrence and spread of micrometastasis. 745.2. COMPLICATIONS RELATED TO THE SURGERY Complication are always depending on the type of surgery, which was perfor-med, but they also differ from patient to patient. We can divide these complicati-on into intraoperative and postoperative. Often the postoperative side- effects result from problems occurred during the surgery. In the past there were some risk factors for complications of the surgery identi-fied. These are subdivided into influenceable and non influenceable. The latter include: age and sex (male) of the patient, low rectum, narrow pelvis. The ASA status plays also a big role in predicting possible complications. As individual risk factors in this group hypertension, coronary artery disease, pulmonary di-sease and obesity stand out. Studies show that elderly have to stay shorter in the hospital and have less surgical side effects if they are laparoscopically ope- !34

rated compared to an open approach. Genderwise males are at increased risk for developing anastomotic leakage and also in developing the general compli-cations. 75Intraoperative accidents have had a slight increase in rectal surgery with advent of laparoscopy. This can be explained by the narrow surgical field and the 2D vision given by most of the screens and the loss of tactile sensation. The difficul-ty to perform laparoscopic surgery on the rectum is shown by the fact that it has the highest conversion rate of all laparoscopic surgeries. The Lesions caused by Intraoperative accidents are pneumoperitoneum, spleen lesions, vascular lesi-ons, lesions to the ureters and the bladder, lesions of lumbosacral and inferior hypogastric nerve plexi and bowel injury itself . 7677Postoperative complications are subdivided into early and late complications. Early complications include anastomotic hemorrhage. It is usually self limited if therapy is needed it has to be surgical. Anastomotic leakage is a common com-plication with an incidence ranging from 3 to 39 %. It is vital to diagnose it im-mediately and the therapy is first conservative, but if it fails a reoperation is nee-ded. Surgical site infection can be involving the skin but also organs or cavities. As risk factors for SSI preoperative hyperglycemia and preoperative temperatu-re are standing out. Antibiotic prophylaxis is indicated to all patients. Late com-plications include anastomotic stenosis, ischemic stenosis and very rarely por-tomesentlric thrombosis. It is crucial to know about those complications and to 78prevent them as much as possible, because especially for the older population the impact on the quality of life is tremendous. 795.3. POST SURGICAL MORTALITY We define post surgical mortality as the appearance of death in patient treated by surgery within the last 30 days. Post surgical mortality is varying a lot bet-ween different hospital sand healthcare systems. A large study in England bet-ween 1998 and 2006 found out that the average mortality was 6,7%. Also in 80other studies the mortality is reported to be around 6 % But the percentage of !35

mortality is decreasing successively with every year. There are multiple risk fac-tors for mortality in the 30 day post surgical period. In the rarest cases the mor-tality is due to a mistake of the surgery itself, but due to co- morbidities. Mortality is increased with age, with co- morbidities appreciated with the Charlson score, in those who live in the most deprived areas and in those treated as emergen-cies. The Charlson score is made up of points of cardiovascular disease, liver disease, malignant disease, renal disease , neurological disease and AIDS. Also man were found to be at higher risk than women. 81Protective factors are a high hospital load and expertise of the surgeon. The adequate surgical approach and of course low Charlson or ASA Score and age. Especially for the elderly laparoscopic surgery is proven to decrease hospital stay and longterm complications, but it is technically more difficult to perform. 82
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PRACTICAL PART

!37

1.APPROACH CONSIDE-RATIONS Rectal cancer is the third most common diagnosed and the second most deadly type of cancer worldwide. It is more prevalent in developed countries, but with the development of former third world countries we see an increase in incidence in developing countries. Also in Romania and in all of the eastern Countries we see a continuously increasing incidence of rectal cancer. The burden of rectal cancer is high and even though there are screening programs the mortality is immense. Furthermore the costs caused by rectal carcinoma are high and need to be carried and paid by the whole society. The diagnosis of rectal cancer is usually followed by a complicated and difficult surgery and treatment with radio or chemotherapy. Due to the necessary invasive and aggressive treatment pati-ents with rectal carcinoma loose a lot of their quality of life and independence. This especially applies to the patients, who are older and already suffer from a variety of comorbidities. For the patients this means that they will have not only a significant physical impact due to the disease and its treatment , but also due to their comorbidties, which can be aggravated in the course of the treatment, but they will also suffer from the psychological impact of having cancer, having to endure the treatment with all its side effects and the possibility of having to live with a colostomy bag for the rest of their life. This triad of the increasing in-cidence, the burden of the disease for the patient itself and the costs which arise from the loss of working power and the treatment for the whole society makes rectal cancer an interesting research topic and makes it crucial to find the best possible treatment for every individual suffering from it. In the search for finding the best treatment solutions I decided on my topic for the thesis with which I hope to find cues about what’s best for the patient. In the ever emerging field of surgery there are plenty of options for the treatment of rectal carcinoma. The best possible surgical approach for the patient should be with a very low of mortality and morbidity, but also with a perfect pathological result and a high quality of life after surgery. For this purpose I compared in my study the laparoscopical and classical approach according to the tumor location !38

within the rectum. There has been already some research about this most known the COLOR and CLASSICC trials, which show the equality between la-paroscopic and classic approach and give the recommendation to tase laparo-scopic approach in patients which are suitable for it. It will be interesting to see if the results obtained in our clinic will differ from the results of the big trials or if they can affirm the hypothesis that the two approaches are equal if chosen right. The aim of the study is to compare the different surgical approaches, the morbi-dity and mortality of the respective approach according to the location of the tu-mor within the rectum. From this comparison we hope to find conclusions for the future treatment of the patients suffering from rectal carcinoma, so that we are able to provide the best possible care in terms of pathological outcome, quality of life and safety of the patient.
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2.MATERIALS AND ME-THODS We conducted a retrospective cohort study, which included 1756 patients, who were surgically treated for rectal carcinoma at Chirurgie III in Cluj- Napoca. The beginning of the data collection was January 2013 and the end December 2018. The inclusion criteria were surgical treatment for rectal cancer with or without neoadjuvant care, all ages and sex, all ASA groups, rural or urban origin, all kinds of presentation at the hospital. During the analysis we excluded patients who were operated multiple times, who were operated for the reestablishment of the GI continuity. The reason for this broad spectrum of inclusion criteria and the lack of exclusion criteria is that we want to be able to have a realistic cross-sec-tion of the patient population treated for rectal cancer and that we hope to find clues about how to choose the right patient fit for laparoscopic surgery and clas-sical approach respectively. By this we expect to find a good comparison bet-ween the different approaches according to the location and a possible guide for the future. The relevant data was taken out of the patient charts, pathology re-cords and the record of the surgery performed. This allowed a detailed analysis of the individual factors of each patient treated, far beyond the subject of this thesis. The patient pool was divided according to location of the tumor in the rectum, which resulted in the categories upper, middle and lower rectal cancer. The three parts are divided according to their distance from the anal verge: the lower rectum is defined as being 0- 6 cm , the middle part 7- 11 cm and the upper rec-tum measuring 12- 15 cm from the anal verge. In these categories we examined the patients regarding on which surgical approach was used, laparoscopic or the classic approach, the origin, rural or urban, age and sex, comorbidities and ASA score, the presenting complaint and the type of presentation at the hospi-tal. Comorbidities recorded were: cardiopathy, diabetes mellitus type I and II, a history of abdominal surgery, metabolic and endocrinological diseases, kidney disease, associated neoplasms, gallbladder stones, colonic polyps, diverticulitis, cirrhosis, gynecological disease, inflammatory bowel diseases and irritable bo- !40

wel disease. The ASA score has the categories 1 to 5. In our patients we found the classes 1- 3. With 1 meaning a healthy patient, 2 a patient with a mild sys-temic disease and 3 a patient with a severe systemic disease, which poses a constant threat to life. Presenting complains in the database are the following: anemia, upper and lower gastrointestinal hemorrhage, constipation, diarrhea, alternating constipation and diarrhea, weight loss, inappetite, pain, tumor forma-tion, tenesmus, sub occlusion, perforation as an acute abdomen emergency. The types of the presentation at the hospital were emergency, stationary after consultation and transfer from another physician. We created subcategories with the three main categories of the localization of the tumor. The subcatego-ries are the two types of surgical approach. Each of those we analyzed accor-ding to intra and postoperative complications, duration of hospital stay, blood loss during the surgery and the need for blood transfusion and mortality. Intra-operative complications recorded were hemorrhage, organ perforation and spleen rupture with subsequent splenectomy. Postoperative complications in-clude the following: suppuration of the suture, hemorrhage, evisceration, acute renal insufficiency, fistula of the anastomosis, cardiac disease symptoms, pos-toperative occlusion, urinary retention, intraabdominal abscess, respiratory symptoms, postoperative hernia formation, thromboembolism, hepatic abscess, fecal incontinence and stenosis of the anastomosis. The mortality was recorded in the period of 30 days after the operation. The methods examined in this study are laparoscopic surgery and the classic approach surgery for rectal cancer. The principle and the goal of the surgery is similar in both types of approaches. The goal is for both of them to completely excise the tumor so that there are clear pathological margins, while providing the best possible quality of life for the patient after the surgery. The principle of the surgeries is for both the mobilization of the left colon, with the following liga-tion of the mesenteric vessels and the complete excision of the mesorectum to provide a perfect oncologic result of the surgery. The approach in laparoscopic surgery is usually done with 5 trocars to provide best possible handling and view. The surgery takes longer, but with a decreased risk of complications, mortality and shorter hospital stay. !41

In the classic approach there is the big abdominal laparotomic incision, which allows a faster operation, but also a higher risk for complications. In the study we will compare those two approaches according to the position of the tumor according to the parameters mentioned above. The data collection was explained above, the analysis of the results was done with Numbers. The categories have significant differences in sample size and a high variance within each group of patients, which made it difficult to use statistical test for the analy-sis of them. In the comparisons done in the thesis we used the Student T- Test with a p- value of 0,05 and the Null Hypothesis stating that there is no significant difference between the two samples tested, to test for a significant difference between the samples.

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3.RESULTS 3.1. PATIENTS In the retrospective cohort study there were 199 patients recorded in 2013, 257 in 2014, 294 in 2015, 304 in 2016, 383 in 2017 and 319 in 2018, which were treated with a surgery for rectal carcinoma at Chirurgie III.
!43Figure 1: Number of rectal cancer patients according to sex and year060120180240
201320142015201620172018
MaleFemale

In the time from 2013 to 2018 there were 1094 male patients and 661 female patients treated surgically for rectal carcinoma at Chirurgie III.
The mean age with which patients were treated at our clinic was 63,43 years old, with a standard deviation of +/- 10,3 years. The mean age for male patients is 63,75 and for female patients 63,05 years old. The mean age is relatively sta-ble over the last five years the aforementioned values.
!44
38 %
62 %MaleFemale
Figure 2: Distribution of sex of rectal carcinoma patients
0125250375500
< 5050- 6060- 7070- 80> 80MaleFemaleMaleFemaleMaleFemaleMaleFemaleMaleFemale
Figure 3: Number of rectal carcinoma patients according to age and sex

In regards to the geographic distribution of the patients we found that 350 pati-ent live in a rural environment and 732 in an urban one.
The distribution of the surgical approach used for the treatment of rectal cancer is 840 patients operated with the classical approach and 242 patients operated laparoscopic.
!45
68 %
32 %Rural Urban
Figure 4: Distribution of the living environment of the patients
22 %
78 %
Classic ApproachLaparoscopic Approach
Figure 5: Distribution of surgical approach used for treatment of rectal cancer

The majority of the patients were operated after consultation and stationary stay at Chirurgie III this group includes 887 patients, the second largest group is made up from emergencies with 150 patients. The smallest group is represen-ted by patients who were transferred to Chirurgie III, 45.
The following were the reason for admission in order of frequency:
!46
4 %
82 %
14 %EmergencyConsultationTransfer
Figure 6: Distribution of the type of admission to the hospital
Figure 7: Reasons for admission in rectal cancer patientsLower GI hemorrhage Weight lossAnemiaPainInappettiteAlternating constipation -diarrheaTumor formationConstipationTenesmusDiarrheaSub- occlusion PerforationUpper GI hemorrhage0150300450600

Those are the comorbidities in order of frequency:
According to the comorbidities the patients were classified with the help of the ASA score. In ASA class 1 there were a total of 45 patients, the majority was found in ASA class 2 with 482 patients and in ASA class 3 there were 138 pati-ents.

!47CardiopathyDiabetes Mellitus IIHistory of abdominal surgeryKidney diseaseMetabolic and endocrinologic diseaseCholecystolithiasisAssociated neoplasmsColorectal diverticulitisPolyps in colonGynecologic diseaseCirrhosisDiabetes Mellitus IIrritable bowel diseaseUlcerative colitisCrohn’s disease 075150225300
Figure 8: Comorbidities in patients with rectal cancer
21 %
72 %
7 %
ASA Class 1ASA Class 2ASA Class 3
Figure 9: Distribution of the patients in the different ASA classes

3.2. LOWER RECTAL CANCER In the time span of 2013 to 2018 there were 436 patients surgically treated for lower rectal carcinoma at Chirurgie III. Out of these 436 patients 122 were ope-rated laparoscopic while the remaining 314 had the classic procedure.
Following there is the graphical presentation of the patients sex and surgical approach used in middle rectal cancer.
!48
72 %
28 %LaparoscopicClassic approach
Figure 10: Distribution of the surgical approaches in patients with lower rectal carcinoma
050100150200
Males LAPMales ClassicFemales LAPFemales Classic
Figure 11: Number of patients according to surgical approach and sex

There is a broad range of complications recorded. We analyzed the complicati-ons according to the surgical approach. There are differences in the frequency of different complications according to the procedure used, however the T- Test comparing the both groups showed no clinical significant difference, p- value >0,05, between the two groups. The laparoscopic approach carries a morbidity of 23% if all the complications are added together, while the classic approach has a morbidity of 29%. Following there will be the top three complications found in patients operated for lower rectal cancer for each of the surgical ap-proach.
For both groups we excluded the category other complications, which were for the laparoscopic group 8 and for the classic group twelve. Not presented in the graph are the less common complications, which are for the laparoscopic ap-proach: Respiratory complications with one time recorded. For the classic ap-proach there was acute kidney insufficiency five times, fistula of the anastomo-sis four times, cardiac complications four times and postoperative occlusion also four times, intra- abdominal abscess, urinary retention and respiratory complica-tions three times each and herniation two times. The intra- operative complication recorded for the classic approach were 24 in-tra- operative hemorrhages and three lesions of the ureter, while there were zero complications recorded in the laparoscopic operated patients. !4907,51522,530
Laparoscopic Operated PatientsClassical Operated Patients
Suture Supp.Urinary Reten.HemorrhageGI OcclusionSuture Supp.EviscerationFigure 12: Number of complications according to surgical approach

Studying the blood loss it is evident that during the classical approach more blood is lost compared to the laparoscopic approach, but the p value calculated with the T- test is bigger than 0,05, so there is no significant difference between the two approaches. In the laparoscopic group eight patients needed intra- ope-rative blood transfusion, while in the classic group there 36 patients, who nee-ded transfusion in the time of the surgery.
The hospital stay was very similar in both groups: Laparoscopic patients stayed on average 11,5 days in the hospital, while classical operated patients stayed 11,1 days on average. From 2013 to 2018 two of the 122 laparoscopic patients died in the 30 days post- operative period, which translates to a 1,6% mortality rate. In the classical operated group there were seven deaths, translating to a 2,2% mortality rate.

!50055110165220
<201201-400>400LaparoscopicClassicLaparoscopicClassicLaparoscopicClassic
Figure 13: Blood loss in laparoscopic and classic operated patients

3.3. MIDDLE RECTAL CANCER From 2013 to 2018 there were 405 patients surgically treated with the diagnosis middle rectal carcinoma. Out of these 405 98 were operated laparoscopic and 307 classical.
In the patients with middle rectal cancer there is no difference in choosing the surgical approach according to the sex of the patient.
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76 %
24 %Number of Patients operated laparoscopicallyNumber of Patients operated classical
Figure 14: Distribution of the surgical approaches with middle rectal cancer
055110165220
Males LAPMales ClassicFemales LAPFemales Classic
Figure 15: Number of patients according to surgical approach and sex

For the complications of middle rectal cancer we found a somewhat statical si-gnificance as the calculated P- value is 0,054, so it is bigger than 0,05, but close enough. The morbidity rate for laparoscopic was calculated to be 14%, while it was 25% in patients operated with the classic approach. In the graph there are the three most frequent complications of the two approaches respectively.
The other complications which are not graphically represented are the following for laparoscopic operated patients: evisceration which appeared one time. For the classical operated patients there are eleven times eviscerations reported, seven times respiratory complications, urinary retention and intra- abdominal abscess each two times and one time stenosis of the anastomosis. Also here we exclude in both groups the category other complications, which counted two complication in the laparoscopic group and 26 in classical group. In laparoscopic operated patients there was one intra- operative complication, which was the perforation of a cavitary organ. On the other hand side in the classical operated there nine cases of intra- operative hemorrhage, two times perforation of a cavitary organ and two times a splenectomy after injury to the spleen was necessary.
 !520612182430
Laparoscopic operated patientsClassic operated patients
Suture Supp.Suture Supp.Post- op. Occ.Fistula Anast.Fistula Anast.Evisceration Figure 16: Number of complications according to approach

As a measure of examining complications we also compared the values for the blood loss in our two groups of patients. Also in the patients with middle rectal carcinoma the P- value is bigger than 0,05 so statistically there is no difference between the two groups. But we also see here that generally in classical opera-ted patients more blood is lost. In the laparoscopic group six patient needed in-tra- operative blood transfusion, while there were eight patient in the classical group who needed blood transfusions.
In the patients operated for middle rectal cancer the hospital stay in the laparo-scopic group was on average 10 days and in the classical operated group it was on average 11,1 days. During the time of the study there was no death recorded in the laparoscopic operated group. In the classical operated group 12 out of the 307 people died, which means a mortality rate of 4%.
!53075150225300
<201 ml201- 400 ml>400mlLaparoscopicClassicLaparoscopicClassicLaparoscopicClassic
Figure 17: Blood loss in laparoscopic and classical operated patients

3.4. UPPER RECTAL CANCER We included in our study 241 patients with the diagnosis upper rectal cancer. Out of these there were 22 operated laparoscopic and 219 with the classical approach.
It is following the surgical approach in males and females for the surgery per-formed on upper rectal cancer.
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91 %
9 %LaparoscopicClassical
Figure 18: Distribution of surgical approach in upper rectal carcinoma
050100150200
Males LAPMales ClassicalFemales LAPFemales Classical
Figure 19: Number of patients according to surgical approach used and sex

In the following graph there will be the three most common post- operative com-plications presented. In the upper rectal cancer category we found that there is a significant difference between the two groups of surgical intervention. The cal-culated P- value was 0,0087 and by this smaller than 0,05. But in the upper rec-tal cancer category the morbidity rate for laparoscopic operations is with 50% much higher than the morbidity rate in the classical operated patients with 28%.
The complications, which are not shown in the graph are the following: two ca-ses of cardiac complications and one case of respiratory complications and post- operative occlusion each for the laparoscopic operated ones and four ca-ses of post- operative hemorrhage, intra- abdominal abscess and cardiac com-plications each, three cases of suture suppuration and urinary retention and two cases of thromboembolism and acute kidney insufficiency each and one case of post- operative occlusion in the classical operated group. Also in this group we excluded the category other complications, which accounted for one case in the laparoscopic and for 15 cases in the classical group. In the laparoscopic group there was one case of intra- operative cavitary organ perforation, while in the classical group there were nine cases of intra- operative hemorrhage, one cavitary organ perforation and two lesions to the spleen, which caused splenectomy.

!5502,557,510
Laparoscopic operatedClassical operatedFigure 20: Number of complications according to approachUrinary Reten.Fistula Anast.Suture Supp.EviscerationAKIRespiratory com.

Also in the upper rectal cancer patients we compared the blood loss of the two types of surgical intervention. Also in this pool of patients we see that the blood loss in the classical operated patients is more compared to the laparoscopic operated ones, but also here the P- value of the T- Test is bigger than 0,05. So there is no clinical significant difference between the two types of surgeries. Two patients in the laparoscopic group and 19 of the classical operated patients re-ceived intra- operatively blood transfusion.
The hospital stay in the laparoscopic operated patients was 11,4 days on avera-ge, while the classical group had an average stay of 10,1 days. In the period of 2013 to 2018 two patients of the laparoscopic groups died, gi-ving a mortality rate of 9%. The mortality rate of the classical operated patients was 4,6%, which means that 10 patients died in the time of the study.

!56050100150200
<201 ml201- 400 ml>400mlLaparoscopicClassic LaparoscopicClassic LaparoscopicClassic
Figure 21: Blood loss in laparoscopic and classic operated patients

4.DISCUSSION The study was comprised of 1756 patients out of which 1094 were men and 661 were women. In our study there was male preponderance of 1,65:1 compared to the female. In the literature there are multiple studies comparing the prevalence of colorectal carcinoma between the two gender, but in those it is stated that the distribution among the sexes is usually approximately equal. Now it is not easy to justify this difference just by coincidence as the difference in the number of male compared to female patients is rowen for every year analyzed. The rea-sons for this increased prevalence among men can be numerous, looking at the typical Romanian alimentation we see a lot of risk factors for the development of rectal carcinoma, women might consume the same kind of food but in lesser quantities than the men. Also alcohol and tobacco consumption was much hig-her in the male population, 485, compared to the female population, 50. Comparing the living environment we found that patients with rectal cancer come 2,1 times more often from an urban environment compared to a rural envi-ronment. Studies show that in all parts of the world, USA, Canada and China this disparity exists. Furthermore these studies show that overall survival is lo-wer in the rural group compared to the urban group. There are different factors causing this difference: The rural communities have often a lack or a very diffi-cult access to health care, medical centers for performing the screening with colonoscopy are only found in bigger cities and usually need to be paid by the person itself. Which can be difficult concerning the average income in rural Ro-mania. Another problem is the lack of education among the rural population about the avoidance of risk factors and the need for annual checkups and screening programs for rectal cancer. So in conclusion we can say that this lo-wer number of rural patients is not solely because the people on the countryside are healthier than the people in the city, but that there are more undiagnosed or late diagnosed patients, who do not have an indication for surgery anymore and of course is the hospital within the city more frequented by the people living in the vicinity of it.
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The average in the patients treated for rectal cancer was 63,4 years. Studies from England also report an average age of 63 years. The biggest part of the patients treated was between 60- 70 years old, which is also according to what other studies found. Analyzing the reasons for admission we assume that those are the first signs and symptoms the patient notices and attributes to a possible neoplasm. In our study the most common reason for admission was lower GI hemorrhage, then loss of weight and followed by anemia. Studies on this topic have a high level of variation, but generally our result fit well within these studies. In some studies changes of bowel habits are the most common reason for admission, while in others blood per rectum and iron deficiency anemia are on the first place. Those signs and symptoms are depending on in which stage the tumor is and what kind of growth it has. The comorbidities reported in the patients treated for rectal cancer were mostly cardiopathies and diabetes mellitus type II. The occurrence and the high preva-lence of comorbidities in general in patients with rectal carcinoma is easily ex-plained by the high age of most of the patients suffering this kind of disease. The frequency and the type of comorbidties are the same as described in other studies. It is to emphasize the problematic of diabetes as it basically stands for an unhealthy lifestyle with a lot of risk factors for rectal cancer including obesity diet high in fats and low in carbohydrates, sedentary life and with increase of circulation growth factor. Furthermore diabetes itself is considered a risk factor for the cancer itself, but also for the development of complications intra and pos-toperative like bleeding disorder and infections and it is harder to perform surge-ry on an obese patient compared to a normal weighted person. The majority of our patients were classified in ASA 2, which means a patient is suffering from a systemic disease, but also ASA 3 were still a substantial part of the patients. This is important to keep in mind when discussing the mobility and mortality and comparing to the result of other studies as these patients are often excluded.
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Lower rectal cancer is defined to be 0- 6 cm from the anal verge. It is difficult to treat surgically no matter if laparoscopically or with the classical approach. It is located deep within the pelvis. This gives a natural very closed and packed for the surgery with the proximity of organs, vasculature and nerves to the incision margins. Furthermore the closeness to the anal sphincter makes it difficult to reach pathological acceptable distal margins without impairing the fecal conti-nence of the patients. We found that 28% of all patients admitted for rectal can-cer were treated with laparoscopic surgery. In literature and studies found there is not really a comparison in frequency of the surgical procedures used for the treatment. However there is con-sense about the safe use of laparoscopic sur-gery for all types of rectal cancer. The Color II trial showed the equality, if the patients chosen for laparoscopic surgery and the surgeon performing the surge-ry are suitable for the surgery. In our study the percentage of males and females chosen for laparoscopic surgery were approximately equal, which show that the narrower male pelvis and the higher number of intra- pelvic organs did not influ-ence the choice of surgical intervention. Comparing the complications, which appeared in both groups of operated patients, with the Student T- test we found a P- value of 0,075, which is slightly higher than 0,05 so we do not have a clini-cal significance for our P- Value. But still there is a recognizable difference bet-ween the two methods. The same statistics were observed by other studies: The group of laparoscopically operated patients generally had fewer intra- and pos-toperatively complications compared to the patients operated classical. The ty-pes and frequency of the complications we found is also comparable to the ones in literature as is the morbidity rate. Unfortunately sexual dysfunction and quality of life were not integrated in our study, which are often found as important mar-kers of complications in other studies. As another marker of the quality of surge-ry we examined the blood loss in both groups and compared it with the help of the Student T- test. We found that there is no clinical significant difference bet-ween the both surgical approaches, but it is evident that in the classical ap-proach there is more blood lost than in the laparoscopic approach. Also this is affirmed by other studies. This finding is logical by looking at the size of the inci-sion that has to be done for the open approach. Furthermore in laparoscopic surgery the view into the narrow pelvis is often better than during the laparotomy and the vascular planes, which have to be incised are easier identified.
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Also due to the better visualization the 

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5.CONCLUSION

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