MINISTRY OF EDUCATION AND TRAINING MINISTRY OF HEALTH HANOI MEDICAL UNIVERSITY HOÀNG MINH ĐỨC RESEARCH ON SURGICAL OUTCOMES AND RISK FACTORS OF RECURRENCE, METASTASIS AFTER CURATIVE SURGERY FOR COLORECTAL CANCER Major: Gastrointestinal surgery Code: 62720125 SUMMARY OF DOCTOR MEDICINE THESIS Hanoi - 2019 THE THESIS IS COMPLETED AT: HANOI MEDICAL UNIVERSITY Scientific advisors: Assoc Prof., Nguyen Thanh Long First opponent: Second opponent: Third opponent: This thesis is defended at University Thesis Examination Council, held at Hanoi Medical University At … hour … minute on … … … 2019 The thesis may be read at following libraries: - National Library of Vietnam; - Library of Hanoi Medical University; INTRODUCTION Colorectal cancer is one of the most common malignancies; according to the 2019 statistics World Health Organization each year there are 1,8 million new cases and almost 861,000 deaths in 2018 Despite recent significant medical advancement in diagnosis and treatment of colorectal cancer in the recent years, recurrence and metastasis after curative surgery for colorectal cancer have still been serious challenges to clinical doctors In the world, there have been a number of researches on postoperative recurrence of colorectal cancer, and these researches show that the rate of recurrence is about 20%-30%, of which 60%-80% of recurrences occur within the first years after surgery Colorectal cancer is classified as recurrent when new malignant lesions are found, either local or metastatic, in patients previously had curative surgery for colorectal cancer Risks of recurrence depend on various factors, of which the major factors are disease stages, surgical features and postoperative adjuvant treatment In order to detect recurrent colorectal cancer, it is necessary to conduct regular postoperative examinations with following clinical and subclinical tests: Carcinoembryonic antigen (CEA) test, liver ultrasound, chest X-ray, flexible colonoscopy - biopsy, CT scan, MRI scan, PET - CT scans, etc For treatment of recurrent colorectal cancer, surgery is still the main treatment method, however whether a surgery is possible depends on site of recurrence and degree of tumor growth Prognosis after surgery for recurrent colorectal cancer depends on various factors, for example time of recurrence after surgery, disease stage, and having adjuvant treatment or not In the recent years, the number of patients diagnosed with recurrent colorectal cancer and underwent surgery has been increasing Nevertheless, in our country researches on this issue are still limited Therefore, researching on surgical outcomes and risk factors of recurrence and metastasis after curative surgery for colorectal cancer is necessary and has scientific implication for the purpose of generalizing features of recurrence, treatment and outcomes of recurrence treatment as well as identifying risk factors of recurrence after surgery for colorectal cancer Objectives of research: Describing features of recurrence, metastasis after curative surgery for colorectal cancer Assessing outcomes of surgery for recurrent and metastatic colorectal cancer Analyzing a number of risk factors of recurrence, metastasis of colorectal cancer CONTRIBUTIONS OF THE THESIS Implications of the thesis Results of this research shall help doctors of Gastrointestinal surgery have more understandings of recurrence of colorectal cancer: Site of recurrence, time of recurrence, metastasis, indication of surgery for recurrent colorectal cancer and early and late outcomes of treatment Also, results of this research identify risk factors of recurrence, such as: Age, disease stage, differentiation, histopathological type, features of tumor growth by Bormann classification, and Petersen index (including various factors: Vascular invasion, serosal invasion, invasion in resection margin, necrotic tumors with perforation), which help surgeons give advises on adjuvant treatment for patients having high risks of recurrence This research has highly practical implications by providing complete information about features of recurrence, indications and methods of surgery and outcomes of treatment of recurrence after curative surgery for colorectal cancer Furthermore, this thesis provides information about risk factors of recurrence, which can make treatment after curative surgery for colorectal cancer be more effective This research has scientific implication with coherent layout and appropriate method of data processing Research data are processed by modern medical algorithm being capable of properly solving the objectives of research This thesis has creative, new and up-to-date features, and is the first research that compares the groups of patients with and without recurrence for the purpose of identifying risk factors of recurrence in Viet Nam Structure of thesis The thesis comprises of 148 pages, with 87 tables, charts, diagrams and 20 images The thesis has chapters: Introduction (2 pages); Chapter - Overview of literature (40 pages); Chapter Subjects and methods of research (15 pages); Chapter - Results of research (36 pages); Chapter - Discussion (50 pages) and Conclusion (2 pages); the thesis has 255 references (18 in Vietnamese, and 255 in English) Chapter 1: OVERVIEW Features of recurrence Definition: Colorectal cancer is classified as recurrent when new malignant lesions are found, either local or metastatic, in patients previously had curative surgery for colorectal cancer, and at the same time the current outcomes of anatomical pathology are similar to that of the previous surgery Features of recurrence: Recurrence may be local (at anastomosis, remaining colorectal section, surgical scar, trocar hole, mesentery, or in the pelvis, etc.) or metastatic (in lung, liver, ovary, peritoneum, etc.) Site of recurrence can be in any intra-abdominal location, isolated or combined with metastasis A recurrent tumor may be local or invades other adjacent organs (invading vessels, kidney, ureter, bladder, uterus, etc.) Rectal cancer has rate of local recurrence (pelvis) higher than that of colon cancer, due to the characteristic of invading surrounding organs in pelvic region via lymphatic system and intravenous system However, application of total mesorectal excision (TME) and new chemoradiotherapy protocol has recently reduce rate of recurrence of rectal cancer to 6% The rate of anastomotic recurrence is - 15% of the total number of patients, including invasive masses outside of rectum and in front of sacrum In contrast, colon cancer has rate of retroperitoneal recurrence higher than that of rectal cancer According to Galandiuk et al., for colon cancer, rate of retroperitoneal recurrence, metastasis within years after surgery of is 15%, and rate of local recurrence is 15%; meanwhile that of rectal cancer is 35% and 5% respectively For rectal cancer, the overall rate of recurrence is about 30% within years after curative surgery The rate of recurrence, metastasis depends on whether the rectal cancer tumor is high or low: The research on 6859 patients treated with surgery for rectal cancer shows that: Comparing to rectal cancer with low tumor, the rate of liver and lung metastases of rectal cancer with high tumor is higher, p=0,03, and there is no difference in the rate of local recurrence Risk factors of recurrence, metastasis - Histopathological type: Adenocarcinoma is the most common histopathological type, accounting for 95% and has prognosis of recurrence better than other types - Disease stage: Is the factor having the most important prognosis value The later the disease stage is, the higher the risk of recurrence is The TNM staging system of the World Health Organization and American Joint Committee on Cancer (AJCC) 8th edition staging system 2018, apart from creating a consensus for oncologists to exchange information, also have prognosis implications The research of Tomoki Yamano on 4992 cases of colorectal cancer shows that the recurrence rates of stages I, II, and III were 1.2%, 13.1%, and 26.3%, respectively (for 3039 colon cancer patients), and 8.4%, 20.0%, and 30.4%, respectively (for 1953 rectal cancer patients) - Differentiation and grade of tumor: Is an independent prognosis factor, in which poor and no differentiation predict high risk of recurrence - Tumor growth based on Borrmann’s classification: B-I/II (gross appearance shows polypoid/ulcerative lesions without infiltration) have better prognosis than B-III/IV (gross appearance shows invasive/infiltrative ulcerated and poorly demarcated lesions) - Lymphatic invasion, vascular invasion: Have bad prognosis - Perineural invasion: Results in increased rate of recurrence and decreased overall survival - Number of dissected lymph nodes and metastatic nodes: When distant metastasis does not present, the extent of lymphatic metastatic spread is the most important factor in prognosis of postoperative survival time and recurrence, metastasis Dissection of lymph nodes must be proper (at least to D2) and radical (at least 10 nodes) in order to evaluate disease stage and obtain better prognosis of recurrence - Conditions of resection margin and total mesorectal excision - TME: Before the time of total mesorectal excision (TME), local recurrence often occur at the remained mesorectum (left after previous surgery) or at the location of anastomosis - Petersen Index: Petersen Index is a multivariable assessment of recurrence risk One score shall be added if each of the following sign present: Venous invasion, serosal invasion, and margin involvement, and scores shall be added if there is perforation through tumor Total score: + 0-1 score: Low risk of recurrence + 2-5 score: High risk of recurrence - Pre-operative CEA before surgery and postoperative follow-up: Means bad prognosis, however this must be combined with other prognosis factors in order to decide on adjuvant treatment after curative surgery After curative surgery, if CEA level does not return to normal, the patient has high risk of recurrence and distant metastasis According to Chau I., follow-up on cases of colorectal cancer after surgery shows that: CEA level being unit higher than the value of the previous examination has prognosis of recurrence in 74% of cases with recurrence - Combination therapy after surgery helps kill the remained cancerous cells Cases treated with combination therapy after surgery have less risk of recurrence - New prognostic factors: Due to development of molecular technique, more and more genes as well as changes in chromosomes are identified as involved in the regulation of cell cycle Some of these factors can help determine progression of disease in order to find appropriate methods of treatment Factors recently being explored include: Thymidylate synthase, microsatellite instability, 18q loss, Kras mutation, DCC, etc Chapter 2: SUBJECTS AND METHODS OF RESEARCH 2.1 Study population - The population for researching on objective and are 53 patients with recurrence who underwent the first surgeries in the years of 2013 and 2014, and the second surgery (for recurrence) at Viet Duc University Hospital - The population for objective include groups: 53 patients with recurrence and 545 patients without recurrence All of these 598 patients underwent their first surgeries in 2013 and 2014 2.1.1 Patient selection criteria - Recurrent cancer treated with curative surgery for colorectal resection: + Having surgical methods or outcomes of anatomical pathology showing colorectal segment with tumor, negative resection margin and dissected lymphatic nodes + Having results of anatomical pathology of carcinoma and current outcomes of anatomical pathology being similar to that of the previous one - Patients with non-recurrent colorectal cancer undergoing surgery for colorectal resection, with clinical and subclinical follow-up and examination not showing recurrent lesions 2.1.2 Patient exclusion criteria: - Medical records being incomplete - Patient with colorectal cancer but in the previous surgery colon was not radically dissected (artificial anus was created without dissecting tumor, bypass, etc.) or cancer cells present microscopically at the resection margin - Patient having other cancerous disease 2.2 Methods of research: Descriptive retrospective research * To solve the objective and 2: We collect data of 53 patients with recurrence undergoing surgeries at Viet Duc University Hospital Of the 53 patients with recurrence, information of the first surgeries and the second surgeries are collected These patients with recurrence is regularly followed up after surgery, with collected information including adjuvant treatment (chemical/radiotherapy), date of recurrence, recurrence location, clinical symptoms, subclinical features, diagnostic, and surgical method * To solve the objective 3: Medical records showing surgery for primary tumor: 598 cases meeting selection criteria are selected and divided into groups of with and without recurrence The group with recurrence has 53 patients and the group without recurrence has 545 patients The two groups are compared using Chi-squared test, Fisher’s or Mann Whitney algorithms on SPSS version 22.0 (SPSS, Inc, Chicago, IL) A difference between the two groups analyzed by log-rank test having P