CURRENT THERAPEUTICS AND PROGNOSTICS ABOUT COLO-RECTAL CANCER -DOCTORAL THESIS- ABSTRACT. PhD Candidate: VASILE F. LIVIU

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1 UNIVERSITY OF MEDICINE AND PHARMACY FROM CRAIOVA MEDICINE FACULTY CURRENT THERAPEUTICS AND PROGNOSTICS ABOUT COLO-RECTAL CANCER -DOCTORAL THESIS- ABSTRACT Scientific Coordinator Ph. D. MD. ION GEORGESCU PhD Candidate: VASILE F. LIVIU Craiova 2010

2 CONTENTS INTRODUCTION... p. 5 PART I CURRENT STATUS OF THE PROBLEM...p.8 CHAPTER I SURGICAL ANATOMY AND PHYSIOLOGY OF COLON AND RECTUM p. 9 I.1. General anatomical description...p. 9 I.2. Surgical anatomy...p.10 I.3. Physiology and consequences of colo-rectal resections...p. 15 CHAPTER II ETHIOPATHOGENY OF COLO-RECTAL CANCER...p.16 II.1. Etiopathogenesis... p.16 CHAPTER III ANATOMOPATHOLOGY OF COLO-RECTAL CANCER...p.24 III.1. Morphopathology of colo-rectal cancer... p.24 III.2. Dissemination of colo-rectal cancer...p.26 III.3. Staging... p.28 CHAPTER IV DIAGNOSTIC OF COLO-RECTAL CANCER...p.31 IV.1. Early diagnosis of colo-rectal cancer... p.32 IV.2. Diagnosis of advanced colo-rectal cancer...p.32 IV.3. Clinical diagnosis of colo-rectal cancer... p.32 IV.4. Paraclinic diagnosis of colo-rectal cancer... p.36 CHAPTER V TREATMENT OF COLO-RECTAL CANCER... p.43 V.1. Surgery... p.43 V.2. Types of colon neoplasm operations... p.45 V.3. Types of rectal neoplasm operations... p.49 V.4. Attitudes towards liver metastases... p.50 V.5. Laparoscopic treatment of colorectal cancer... p.51 V.6. Complement adjuvant and neoadjuvant treatment of colo-rectal cancer.p.52 PART II PERSONAL RESEARCH...p.54 CHAPTER VI IMPORTANCE OF ISSUE. MOTIVATION AND OBJECTIVES...p.55 CHAPTER VII EPIDEMIOLOGY OF COLO-RECTAL CANCER...p.59 CHAPTER VIII DIAGNOSTIC AND THERAPEUTIC STRATEGIES IN COL-ORECTAL CANCER......p.69 VIII.1. MATERIAL AND METHODS...p.70 VIII.2. RESULTS...p.76 VIII.3. DISCUSSIONS...p.102 CONCLUSIONS...p.162 BIBLIOGRAPHY...p.169 2

3 KEY WORDS: colorectal cancer, colorectal resection, colectomy, total mesorect excision. INTRODUCTION News investigations in the field of colorectal cancer (CRC) has been imposed by the continuous increase of the incidence of disease in developed countries, which already register high levels of prevalence and also in countries formerly where the rates increase gradually. Need to this study are represented by detection and prevention of CRC who remains with no doubt a major problem of public health. Decade was the decade of CRC detection and prevention, and the decade is the period of application of new diagnostic and therapeutic concepts. OBJECTIVES This paper presents in the first part the state of the problem, analyze the dates of classical and modern anatomy, epidemiology and etiopathogeny, pathology, cancer diagnostic and therapeutic attitude in this disease. Part II of the paper entitled "Personal research includes the study of aspects of current therapeutic strategies proposed for colorectal cancer and their prognosis. The objectives of this paper, entitled "Current therapeutics and prognostics about colo-rectal cancer, were: 1. epidemiological knowledge of colorectal cancer in the country and the region; 2. achieving a modern prospective study on colorectal cancer diagnosis; 3. retrospective study of diagnostic and therapeutic strategies for colorectal cancer, 4. retrospective study on the survival of the group with colorectal cancer according to demographic parameters, clinics, morphological, stage and therapeutic; 5. comparing their results with the literature research; 6. deduction of conclusions from the analysis of case law targets studied. 3

4 MATERIAL AND METHODS A. Material We studied prospectively and retrospectively 134 patients with colorectal cancer, who underwent tumor resection, in Emergency County Hospital of Craiova in all three clinics of general surgery, from January 2003 until December The study cohort represented the period of three years. Centralization of the lot, both demographically and pathologically was facilitated by database Pathology Clinical Emergency County Hospital Craiova and thus this prospective study to identify cases of colorectal cancer, their evolution reported to the clinical, pathological, anatomic and therapeutic highlighted. B. Method Processed results from the observation sheets, discharge sheet of the patients and histopathological examination papers. Data on survival at July when ending the tracking of patients in the lot - came from the Registry of Civil Status of the Office of Evidence of Populations from Craiova. Inclusion criteria were the diagnosis of colon or rectal cancer, pre-or postoperatively, with histopathological confirmation and type of surgical resection. Cases were excluded from the study who underwent endoscopic treatment, cases in which colorectal tumor could not be extirpated, those where the intervention of colorectal resection was performed for diseases such as familial adenomatous polyposis, reintegration in transit after previous interventions (Hartmann) and those without resection followed by anastomosis (like lateral colostomy in colorectal cancers, presented in bowel obstruction). After primary selection, patients were studied in groups according to the parameter sought: demographic data, clinical data, staging, morphological, therapeutic data. Related to these parameters, prognosis and survival of patients was examined in the batch. For statistical processing of data were used the following types of statistical tests: tests to measure the dependence between the parameters (chi squared) and significance tests (Student, Anova, Wilcoxon and log-rank). The main statistical analysis software packages were Microsoft Excel 2003 and Epi Info Were drawn by Kaplan-Meier survival curves. 4

5 RESULTS Analysis of 134 hospitalized cases of CRC and resected in SCJU Craiova, between January December 2005 revealed some important demographic survival at 5 years after surgery. From the initial group of 302 patients identified with CRC, noted a significant increase in the incidence with 29.88% (p <0.05) in 2005 compared to 2003, which can be explained by the general trend of development of this malignancies, but also by the fact that the population is increasing the reach of gastroenterology, surgery and oncology specialist services. However, in the cohort studied to show a downward trend in the number of cases with tumor resection is practiced by 45.9% (p <0.05) in for the same reasons, or patients presenting in an advanced stage of disease in which tumor resection is not curative. Analyzing group, 51 patients were alive at July , time of survived on average was / months. The remaining 83 patients who died before that date, had a disease-free interval of / months. The average duration of survival of the entire group is / months. Comparing the overall survival in months during year reported in surgery, we see that the 61 patients operated on in 2003 lived, on average / months, the 40 in 2004, with / months and the 33 in 2005, with / months, these values have no statistical significance (p <0.05). The average duration of survival ranged from / months in the right hemicolectomy, / -4.9 months in the left hemicolectomy, / months in the amputation of the rectum, / months in the subtotal colectomy, / months in the recto-sigmoidian resections and / months in the transverse colectomy, these values were not significant. TMN staging of the 134 patients with CRC who underwent tumor resection revealed as expected, the high percentage of survivors of stage I (four patients %), followed by those in stage II (11 patients - 73, 33%) % of stage III patients have survived at the end of prospects, while no patient in stage IV was not found at July

6 CONCLUSIONS Colorectal cancer is the third cancer in frequency in men (663,000 cases, representing 10.0% of all malignancies) and second in women (570,000 cases, 9.4% of all malignancies) worldwide. News research into colorectal cancer is imposed by a continued increase in the incidence of disease in developed countries, which already register high levels of prevalence, and also in countries formerly were CRC rates are increasing. Early diagnosis of colorectal cancer should become easier as the application, although it is difficult to implement national technical reasons, demographic, organizational, and high cost. Increased incidence of CRC associated with increases in both prevalence and mortality of this disease, suggesting that current methods of treatment, only few cases are actually curable, with a tendency to heal, rest is only temporary extension interventions to limit disease. In Romania, between , CRC occupies second place among cancers in men (after lung cancer) and third in women (after breast cancer and cervical cancer). Increased incidence of colorectal cancer and the declining number of cases with tumor resection practiced between could be explained by the broader public access to the methods of early diagnosis of CRC, early stage endoscopic treatment, or patients presenting in an advanced stage of disease and the tumor resection is not practicable. The distribution by sex, throughout the period studied, shows the predominance of male cases, compared with a general B / F = 1,43:1, declining 43.33% between After the environment of origin, we found a ratio urban / rural = 79/55 = Age range was between 33 and 91 years, with an average of / years. 82 patients (61.19%) were aged between years. The best average survival time was in the decade years ( / months). The age of patients is a very highly significant prognostic factor in patients with CRC statistically. 6

7 69 (51.49%) of surgeries were performed in the emergency thanks of complications showed by patients on admission and 65 (48.5%) elective interventions were practiced. The location of the tumor revealed that 88 (65.6%) patients had colon cancer and 43 (34.3%) rectal tumors. There were no significant associations of elderly with proximal locations of CCR and no report of the phenomenon of "migration" to proximal. Postoperative complications, local - septic or technical - and general are the privilege of emergency surgery, but also of elderly patients. Macroscopically, infiltrative and ulcerated-vegetant forms are most frequently found in equal numbers. Microscopically, we met in order the following types of adenocarcinoma: tubular, mucipar, papillary and other microscopic forms (stromal tumors, sarcomas, etc.). The best survival it is at patients who had a ADK G1 grading, with a months averaging life expentancy, followed by those with ADK G2. TMN staging of casas show that the stage III are the large (74 cases %), followed by stage IV (40 cases %), stage II (15 cases %) and stage I, which is lowest number of cases (5 cases %). The average length of survival of the entire batch of 134 cases was / months. Factors that contribute to a favorable prognosis in CRC are female gender, urban environement origin, younger than 50 years, the absence of disease or complications associated with neoplasia, colic locations, elective surgery, vegetant and papillary forms, G1 and G2 grading and the disease diagnosed in TMN stages I and II. CURICULUM VITAE First name/last name: LIVIU VASILE Date and Place of Birth: , Slatina, OLT county Marital Status: married, 1 child Phone: Electronic Mail: vliviu777@yahoo.com Education: - RADU GRECEANU High School, SLATINA, Olt, , - University of Medicine and Pharmacy from Craiova, , - General Surgery resident, Emergency County Hospital from Craiova, , 7

8 - General Surgery specialist, Emergency County Hospital from Craiova, , - Assistant Teaching, University of Medicine and Pharmacy from Craiova, present, - Obstetric Gynecology resident, Emergency County Hospital from Craiova, present. Competences: -Diagnostic Digestive Endoscopy Member in societies: -Romanian Society of Surgery -Society of Coloproctology of Yugoslavia - Endoscopic Surgery Romanian Association Courses: -2 long term courses of Laparoscopic surgery -1 long term course- Digestive Endoscopy Congresses: -Congresses and Conferences organized by National Societies:14 participations -International Congresses and Conferences: 6 participations Books published: 1. Semiologie chirurgicală. Elemente de curs, Ediia li-a revizuită, I. Vasile, M. Munteanu, M. Paalega, I. Gugilă,, Editura SITECH, 2006, Craiova, 352 pagini, ISBN: (coautor). 2. Semiologie chirurgicală. Manual pentru studeni., I. Vasile, M. Munteanu, M. Paalega, I. Gugilă, Editura Medicală Universitară Craiova, Craiova, 2005, 349 pagini, ISBN: (coautor). Published articles author: 1. Colon cancer trends , L. Vasile, M. Munteanu, P. Mănescu, M. Pîrscoveanu, Anca Ruxanda, t. Dina, L. Drăgusin, Simona Fulger, C. Tudorascu, C. Tenea; 7 th International Symposium of Colo-Proctology, October, 07-09, 2010, Belgrad, Serbia. 2. Rezultate pe termen lung în intervenţiile chirurgicale de urgenţă pentru cancerul de colon, comparativ cu intervenţiile chirurgicale programate, Vasile Liviu, M. Munteanu, P. Mănescu, M. Pîrşcoveanu, Anca Ruxanda, S. Dina, Congresul Naţional de Chirurgie. Ediţia a-xxv-a. Cluj- Napoca. 3-6 mai 2010, Chirurgia, Număr special, Vol. 105,Supliment 1, mai, 2010, pag.127. ISSN: Cancerul colo-rectal complicaţii ale actului chirurgical, L. Vasile, M. Munteanu, P. Manescu, M. Pîrscoveanu, Anca Ruxanda, S. Dina, N. Pogoran, D. Manescu, Simona Fulger, C. Tudorascu, L. Drăguşin, Conferinţa Naţionala de Chirurgie Tg. Mureş mai 2009, Chirurgia, Număr special, Vol. 104,Supliment 1, mai, 2009, pag. 24. ISSN: Acute pancreatitis-nutritional strategies, Vasile L., Munteanu M., Mănescu P., 4th Serbian-Romanian Surgical Conference, Zrenjanin, noiembrie IS ANASTOMOTIC LEAKAGE PREDICTIVE FOR DECREASED SURVIVAL AFTER RESECTION FOR COLORECTAL CANCER? L.Vasile, M.Munteanu, P.Mănescu, St.Dina, M.Pîrcoveanu, Anca Ruxanda, Simona Fulger, D.Mănescu C.Tudoracu, UMF Craiova, 3rd Romanian-Serbian Surgical Conference, Craiova 6-8 noiembrie

9 6. Cancerul colo-rectal atitudine chirurgicală în urgenă, Vasile L., Munteanu M., Mănescu P., Ruxanda Anca, Pîrcoveanu M., Dina t.,mănescu D., Gugilă I., Fulger Simona, Chirurgia, Număr special, Vol. 103, Supliment 1, iunie, 2008, Pag. 108.ISSN: Aspecte etiopatogenice, diagnostice i terapeutice în leziunile traumatice ale duodenului, Vasile L., Munteanu M., Mănescu P., Ruxanda Anca, Pîrcoveanu M., Dina t.,mănescu D., Gugilă I., Fulger Simona, Chirurgia, Număr special, Vol. 103,Supliment 1, iunie, 2008, Pag ISSN: PANCREATITA ACUTĂ RECIDIVATĂ ASPECTE CLINICE ŞI TERAPEUTICE Vasile L., Munteanu M., Mănescu P., Gugilă I., Ruxanda Anca, Pîrşcoveanu M., Dina Şt, Munteanu A. U.M.F. din Craiova, S.C.J.U. Craiova ZILELE UMF A RARE CAUSE OF UPPER DIGESTIVE TRACT BLEEDING PANCREATIC PAPILLARY ADENOCARCINOMA, L.Vasile, M.Munteanu, M.Parscoveanu, P.Manescu, A.Ruxanda, St.Dina, D.Manescu, S.Fulger, C.Tudorascu, I.Gugila Second International Conference of Serbian and Romanian Surgeons, Kladovo, Serbia, november COLORECTAL CANCER EMERGENCY SURGICAL ATITUDE, L.Vasile, M.Munteanu, M.Parscoveanu, P.Manescu, A.Ruxanda, St.Dina, D.Manescu, S.Fulger, C.Tudoracu, I.Gugila Second International Conference of Serbian and Romanian Surgeons, Kladovo, Serbia, november Published articles co-author: 1. Tumorã stromalã gastrointestinalã (GIST) cu localizare cecalã - cauzã rarã de invaginaţie ileo-ceco-colicã, M. Pîrşcoveanu, M. Munteanu, P. Mãnescu, A. Ruxanda, L. Vasile, Şt. Dina, N. Pogoran, D. Mãnescu, C. Tudoraşcu, S. Fulger, L. Drãguşin, Clinica Chirurgie III, UMF Craiova, Chirurgia (Bucur) 2010;105(3): Upper gastrointestinal bleeding of tumoral etiology, Munteanu A.C., Munteanu M,,Mănescu P.,Pircoveanu M.,, Vasile L., Pogoran Nicoleta, Fulger Simona, Chirurgia, Număr special, Vol. 105,Supliment 1, mai, 2010, pag.34. ISSN: Dificultăi de diagnostic i tratament în chistul hidatic hepatic rupt în arborele biliar, Pîrcoveanu M., Munteanu M., Mănescu P.,,Ruxanda Anca, Vasile L.,,Dina t., Pogoran Nicoleta, tudoracu C., Mănescu D., Fulger Simona, Drăguin L.,, pag 127 Chirurgia, Număr special, Vol. 105,Supliment 1, mai, 2010, pag.127. ISSN: Tuberculoza abdominală - cauză de abdomen acut chirurgical, M. Pîrcoveanu, Munteanu M., Mănescu P., Ruxanda Anca, Vasile L., Dina t.,pogoran Nicoleta, Mănescu D, Tudoracu C., Chirurgia, Număr special, Vol. 103, Supliment 1,iunie, 2008, Pag SSN: Managementul chirurgical al hemoragiei digestive superioare-trecut i prezent, M. Munteanu. Fulger Simona, Munteanu AC, Pîrcoveanu M.,Ruxanda Anca, Mănescu P., Pogoran Nicoleta, Vasile L., Mănescu D.,'I'udoracu C., Chirurgia, Număr special, Vol. 103, Supliment 1, iunie, 2008, Pag SSN: Biopsia ganglionului santinelă i limfadenectomia axilara în cancerul de sân puin avansat. Experienta Clinicii III Chirurgie, Ruxanda Anca, M. Munteanu Fulger Simona, Pîrcoveanu M., Mănescu P.,Pogoran Nicoleta, Vasile L., Mănescu D, Tudoracu C.,, Chirurgia, Număr special, Vol. 103, Supliment 1, iunie, 2008, Pag. 230.lSSN: lleus biliar prin calcul inclavat în diverticulită pseudotumorală sigmoidiană, Dina t.., M. Munteanu, Fulger Simona, Pîrcoveanu M.. Ruxanda Anca,Mănescu P., 9

10 Pogoran Nicoleta, Vasile L., Mănescu D, Tudoracu C., Chirurgia, Număr special, Vol. 103, Supliment 1, iunie, 2008, Pag SSN: SURGICAL MANAGEMENT OF RESIDUAL LIVER HYDATID CAVITY- M.Pîrcoveanu, M.Munteanu, P.Mănescu, Anca Ruxanda, L.Vasile, St.Dina, N.Pogoran, C.Tudorascu, D.Mănescu, Simona Fulger, I.Gugilă, UMF Craiova, 3rd Romanian-Serbian Surgical Conference,Craiova 6-8 noiembrie EVOLUTION OF SURGICAL TREATMENT IN UPPER GASTRO-INTESTINAL BLEEDING - M.Munteanu, Simona Fulger, A.C.Munteanu, M.Pîrcoveanu, Anca Ruxanda, P.Mănescu, Nicoleta Pogoran, L.Vasile, D.Mănescu C.Tudorascu, UMF Craiova, 3rd Romanian-Serbian Surgical Conference,Craiova 6-8 noiembrie Histopathologic aspects in the superior gastric pole adenocarcinoma - P.Mănescu, M.Munteanu, D.Mănescu, M.Pîrcoveanu, L.Vasile, St.Dina, Anca Ruxanda, Simona Fulger, Nicoleta.Pogoran, C.Tudorascu, I.Gugilă, UMF Craiova, 3rd Romanian-Serbian Surgical Conference,Craiova 6-8 noiembrie Implication of her-2 protein in breast cancer- Anca Ruxanda, Zorica-Ileana Hertzog, M.Munteanu, P.Mănescu, L.Vasile, M.Pîrcoveanu, St.Dina. UMF Craiova, 3rd Romanian-Serbian Surgical Conference,Craiova 6-8 noiembrie SIMPATECTOMIA LOMBARA(S.L.) METODA DE TRATAMENT IN ISCHEMIILE PERIFERICE Mănescu D., Mănescu P., Munteanu M., Fulger S., Tudorascu C., Pîrcoveanu M., Vasile L., Ruxanda A., Dina S., Pogoran N., Gugilă I. Clinica Chirurgie III, U.M.F. din Craiova, ZILELE UMF RETROPERITONEAL MALIGNANT SCHWANNOMA WITH MULTIPLE INTRAPERITONEAL RELAPSES M.Munteanu, A.C.Munteanu, M.C.Munteanu, M.Parscoveanu, P.Manescu, A.Ruxanda, St.Dina, L.Vasile, D.Manescu, S.Fulger, C.Tudorascu, I.Gugila- Second International Conference of Serbian and Romanian Surgeons, Kladovo, Serbia, november CLINICAL AND HISTOLOGICAL CORRELATION IN THE SUPERIOR GASTRIC POLE ADENOCARCINOMA P.Manescu, C.Margaritescu, M.Munteanu, D.Manescu, M.Parscoveanu, L.Vasile, I.Gugilă- Second International Conference of Serbian and Romanian Surgeons, Kladovo, Serbia, november THERAPEUTICAL AND DIAGNOSTIC CONSIDERATION IN COMPLICATED LIVER HYDATID CYST- M.Parscoveanu, M.Munteanu, P.Manescu, A.Ruxanda, L.Vasile, St.Dina, C.Tudorascu, D.Manescu, S.Fulger, I.Gugila- Second International Conference of Serbian and Romanian Surgeons, Kladovo, Serbia, november Pancreatita acută atitudine terapeutica i rezultate imediate M. Munteanu, M. Pîrcoveanu, P. Mănescu, L. Vasile, Anca Ruxanda, t. Dina,I. Gugilă, A. Munteanu, A. Săftoiu, M. Popescu, Rodica Dilof, Violeta lordache, Craiova Medicală, Revista Universitaii de Medicina i Farmacie, Editura Medicală Universitară Craiova,Volumul 7, Nr. 3, 2005, pag ,1SSN: Evoluie particulară aunui caz de pancreatită acută, M. Munteanu, P. Mănescu, Anca Ruxanda, M. Pîrcoveanu, L. Vasile,,t. Dina,T. Zavate, Violeta lordache, A. Săftoiu, M. Popescu, 1. Gugila, I, Craiova Medicală, Revista Universitaii de Medicinăi Farmacie, Editura Medicală Universitară Craiova, Volumul 7, Nr. 2, 2005, pag , ISSN: