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MINISTRY OF EDUCATION AND TRAINING MINISTRY OF DEFENCE VIETNAMESE MILITARY MEDICAL ACADEMY PHAM VAN BINH THE STUDY IN APPLICATION OF LAPAROSCOPIC ABDOMINOPERINEAL RESECTION FOR TREATMENT OF LOW RECTAL CANCER Speciality: Gastrointestinal surgery Code: 62 72 01 25 Ph.D THESIS ABSTRACT HÀ NỘI - 2013 The thesis was completed in: Vietnamese Military Medical Academy Scientific supervisors: 1. Assistant Professor, Ph.D: Nguyễn Văn Xuyên 2. Assistant Professor, Ph.D: Nguyễn Văn Hiếu Thesis reviewer 1: Prof. HA VAN QUYET Thesis reviewer 2: Assoc Prof. PHAM DUC HUAN Thesis reviewer 3: Assoc Prof. TRIEU TRIEU DUONG The thesis was defended at the Council of Military Medical Academy at 13h30, 03/10/2013 Thesis can be found at: 1. National Library 2. Library of Military Medical Academy 1 Introduction Rectal cancer is one of the common cancers, accounting for nearly a third of the colorectal cancer. Morbidity and mortality of colorectal cancer tend to increase on the world. Today, multidisciplinary treatment of rectal cancer includes surgery, chemotherapy and radiotherapy... in which surgery plays an important role. For over two decades, laparoscopic surgery has clear advantages including less postoperative pain, faster recovery, shorter hospital stay. However, there are some questions: Could laparoscopic surgery achieve lymphadenectomy in oncologic principle? What is survival, recurrence, metastasis rate? At the present, studies on laparoscopic abdominoperineal resection under two aspects including lymphadenectomy and postoperative outcomes on the world as well as in Vietnam remain limited. Due to the above issues, we implemented the study "The study in application of laparoscopic abdominoperineal resection for treatment of low rectal cancer" with 2 goals: 1. Study lymphadenectomy in laparoscopic abdominoperineal resection for treatment of low rectal cancer. 2. Evaluate results of laparoscopic abdominoperineal resection (LAPR) for treatment of low rectal cancer and some factors associated with survival. New main scientific contribution of the thesis Thesis is done at K Hospital – Biggest Cancer Center in Vietnam for studying lymphadenectomy and evaluating the results of LAPR for treatment of low rectal cancer. The thesis reports lymphadenectomy results of laparoscopic surgery ensures oncology principles through analysis of number of harvested lymph-nodes. The average harvested lymph-nodes is 14.6 per patient. Among them, there are 5.5 mesenteric lymph nodes, 5.4 lymph nodes near tumor; 3.7 lymph nodes (LN) of 2 superior rectal artery. The overall rate of lymph node metastasis is 31.11%. Stage N1 is 17.78%, N2a is 2.22%, and N2b is 11.11%. Metastasis rate of 1 LN station was 14.1%, 2 LN stations is 9.6%, 3 stations is 7.4%. Patients treated with preoperative radiotherapy have less harvested lymph-nodes and lower rate of lymph node metastasis. Thesis reports early results in term of surgery: average duration of surgery is 133 minutes, average blood loss is 13, 6 ml, accident rate is 1.48%, complication rate is 2.8%, no open conversion surgery and no intraoperative and postoperative death. The long- term results in terms of oncology is good. Average postoperative survival rate is 33.3 months. There is no local recurrence and metastasis. Preoperative radiotherapy, lymph node metastasis, stage of disease and age are some factors related to postoperative survival rate. STRUCTURE OF THE THESIS The thesis consists of 123 pages: 2 introduction pages, 39 background pages, 19 pages for study methods, 24 pages for results, 37 discussion pages, 2 pages for conclusion. There are 37 tables, 16 diagrams, 24 pictures, and 149 references, including 30 in Vietnamese, 119 in foreign languages. CHAPTER 1 – OVERVIEW 1.1. Anatomy application in rectal cancer surgery 1.1.1. Anatomical landmarks: The rectum is the last segment of the gastrointestinal tract connecting with sigmoid colon at the third sacral vertebra and ending at the edge of the anus. 1.1.2. Mesentery of rectum: Mesentery of rectum, fat fiber tissue is located within the limits of the rectal muscle and visceral perineum of pelvis, covering 3/4 3 circumference of the rectum. 1.1.3. Nerve, blood vessels of the rectum: The rectum is supplied by 3 main vessel bundles: superior rectal, middle rectal, and inferior rectal artery. Autonomic nerve control rectal secretions, motor nerves control movement of anal sphincter. 1.1.4. The lymphatics of the rectum: * Lymphatics of mesentery of rectum * Lymphatics of ischiorectal cavity * Lymphatics of rectal wall peritoneum. Lymphatic drainage: * Lymphatic vessels from superior half of rectum drain to para rectal nodes and from there to inferior mesenteric and lumbar nodes * Lymphatic vessels from the inferior half of the rectum Travel with the middle rectal vessels to the internal iliac nodes Anastomose with the lymphatics of the anal canal 1.2. Histopathology of rectal cancer 1.2.1. Gross appearance: ulcers, infiltration and other type. 1.2.2. Micro appearance: Classification by the World Health Organization (WHO 2000): Adenocarcinoma accounting for over 98%, carcinoid tumors, lymphoma, mesenchymal tumors, GIST, Kaposi Sarcoma. 1.2.3. The natural progression of colorectal cancer: Cancer cells spread along the gastrointestinal tract into the submucosal layer. From primary tumor, cancer cells can spread to regional lymph nodes and distant metastases to the liver, lungs, brain as well as invade nearby organs. 4 1.2.4. Evaluating stage of rectal cancer E. Dukes offer the common, simple staging system. In 1954, the AJCC established TNM system for stage evaluation for most cancers. 1.3. Diagnosis of rectal cancer 1.3.1. Signs and Symptoms: Abdominal pain, bowel habit change. Digital rectal examination is important to assess rectal tumors. 1.3.2. Investigations: * Colorectal endoscopy: biopsy to identify histopathology. * Diagnostic Imaging: X-ray of the colon with radio-contrast agent has switched to endoscopy, abdominal ultrasound to find out liver, peritoneal metastasis. Endorectal ultrasound assess T stage and N stage. CT scanner is accurate for T stage from 50% to 90%, for N stage from 70% to 80%. Pelvis magnetic resonance imaging (MRI) evaluate T stage and N stage with a sensitivity of 95%, a specificity of 90%. PET-CT find out early postoperative recurrence and distant metastasis. * CEA: Monitoring local recurrence and distant metastasis. 1.4. Treatment of rectal cancer 1.4.1. Surgery Principles of radical surgery (R0) * Remove entire primary rectal tumor. * Remove invaded organs as well as metastatic lesions. * Lymph nodes dissection. Surgical types: depend on disease stage, patient condition, the ability of the surgeon. According to the nature of the treatment, the type of surgery: * Radical surgery 5 * Pelvic exenteration surgery * Palliative surgery The open surgery of rectal cancer: * Transanal tumor resection * Low anterior resection * Abdominoperineal Resection * Surgery for complications of rectal cancer The laparoscopic surgery of rectal cancer: Today, with the perfection of surgery skills and endoscopic equipment, all open surgery of rectal cancer is switched to laparoscopic surgery. * Laparoscopic low anterior resection. * LAPR. * Hartmann Surgery. * Sphincter preservation surgery. 1.5. Adjuvant treatment for rectal cancer: * Chemotherapy: improving survival. * Radiotherapy: reducing the incidence of local recurrence and improving disease free survival, so multidisciplinary treatment have become the standard treatment in rectal cancer. 1.6. Study situation of LAPR on the world and inVietnam 1.6.1. On the world The number of LAPR studies are limited. * In 2005, Aziz.O review literature from 1993 to 2004. There are 22 studies with 2071 patients, only 8 studies mentioned laparoscopic lymphadenectomy in LAPR. * According to major report by Wiley Publishers in 2008, there are 33 clinical trials from 1988 to 2007 on 46 medical journals, among them 6 studies on 6 lymphadenectomy in LAPR, 12 studies on 5 year survival in LAPR with 3346 patients. * Lourenco.T, Health Research Institute of Britain in 2008 review laparoscopic surgery compared with open surgery on 4500 patients from 1997 to 2005 on the world. 12 studies mentioned lymphadenectomy but did not regard to LAPR. Some larger ongoing study on LAPR: * Study of Japan Cancer Research Group will finish by 2014. * European Colorectal Cancer Research Group will finish by 2017. * Study of United States Cancer Surgeon Association is going to report in 2013. 1.6.2. In Vietnam From 2003 to 2012, mainly focusing on perfecting surgical techniques such as removal of entire mesentery of rectum, preservation of nerves and urogenital fuction. Recently there have been some researches on LAPR. But these has not really focused on the role of lymphadenectomy and postoperative results. Thus LAPR still need further studies to confirm that LAPR is a standard option in the treatment of low rectal cancer. CHAPTER 2 - SUBJECTS AND METHODS 2.1. Study subjects: Patients with low rectal cancer at K Hospital from 01/01/2009 to 31/12/2011 underwent curative LAPR, follow up to 30/06/2012. 2.2. Research Methodology 2.2.1. Methods: prospective descriptive study (cross-sectional non-control). 2.2.2. The formula for calculating sample size: The minimum sample size was calculated as following: 7 n = (1.96) 2 x 0.056 x 0.944 / (0.05) 2 = 81.2 patients According this above formula, minimum sample size are 82 patients. 2.3. The study targets: the clinical, pathological, investigation characteristics 2.3.1. The clinical characteristics 2.3.2. The pathological, investigation characteristic 2.4. LAPR and lymphadenectomy process 2.5. Assessment results 2.5.1 Lymphadenectomy results * Total number of harvested lymph-nodes on 135 patients. * The average number of lymph nodes per 1 patient (mesenteric lymph nodes, lymph nodes near tumor, lymph nodes of superior rectal artery). * Overall rate of lymph node metastasis, metastasis rate of LN stations, LN stages. * The average number of lymph nodes per 1 patient and lymph node metastasis rate of patients with and without receiving preoperative radiotherapy.. 2.5.2 Early Results * Operation time, estimated blood loss. * The surgical complications: bleeding, urinary, intestinal damage. * The postoperative complications: bleeding, intestinal obstruction, infection, abscesses, bladder paralysis ... * Time using IV or IM algenesthesia, bowel peristalsis, and length of hospital stay. 8 * Mortality due to surgery: in 30 days after surgery. 2.5.3. Delayed results and some related factors The postoperative survival by Kaplan-Meier Postoperative follow up every 3 months for first year, followed by every 6 months in next 2 years, and every year from the fifth year. Results of treatment at the end of the study: * Number of alive patients, died patient. * Rate of local recurrence, distant metastasis, trocar holes recurrence. * The median survival. * The average survival at 6 months, 12 months, 24 months, 36 months. Analysis on factors related to survival * Age ≤ 60 years and> 60 years old. * Disease stage. * N stage. * Preoperative Radiotherapy. 2.6. Data Analysis: Data were collected from medical records. All the data is analyzed by Excel 5.0 and SPSS 15.0. Evaluating postoperative survival rate by Kaplan-Meier method. Compare the differences between quantitative variants by T test, and categorical variants by chi-square test with 95% accuracy (p <.05). CHAPTER 3 – RESULTS 3.1. General Characteristics * Age, sex: 135 patients with mean age 55.3. 69 male, 66 female. Rural: 98 Urban: 37. 9 * The average time from onset of symptoms until having diagnosis is 3.8 ± 1.2 months, 14.07% of patients having a previous operative scar. 3.2. Clinical Characteristics * Symptoms: abdominal pain, tenesmus, blood mixed with stool accounting for 97.78%. * Digital rectal examination: 1 to 3cm distance from tumor to anus accounting for 94.81% , 68.89% tumors involved 1/2 to 2/3 of the circumference; limited motion tumors accounting for 35.56%. 3.3. Investigation characteristics: * The preoperative tests: blood count, biochemistry were normal range, 2.9% of patients have CEA level higher than 50ng/ml. * Rectoscopy results: 1 to 3cm distance from tumor to anus accounting for 96.29% of patients, 98.52% tumors tumors involved 1/2 to whole of the circumference; 54.8% to ulcerative tumor, moderate differentiated adenocarcinoma accounting for 61.5%. * CT scanners: 14.8% of patients were given CT scanners, it showed 40% of patients having lymph node metastasis. * Magnetic resonance imaging (MRI): serosa invasive tumors accounting for 99.26% , lymph node metastasis rate was 27.4%, 27.41% of patients is stage III, 14.81% patients is stage IIB, and 57.78% for stage IIA. * Endorectal Ultrasound: 18.5% of patients were done. 100% of patients is stage T3, 40% patients had lymph node metastatic image. * The histopathology results: 100% tumors are invasive, 97.04% tumors have 1 to 3cm distance from tumor to anus, tumor size from 2 to 5 cm accounting for 95.6%; serosa invasive tumors accounting for 57.78% , and T4 stage is 42.22%. 3.4. Treatment before and after surgery: 10 35.55% of patients underwent preoperative radiotherapy, 42.22% of patients received adjuvant chemotherapy. 3.5. Lymphadenectomy Results Table 3.15: Average number of lymph nodes classified according to dissection sites. Radiotherapy n Lymph nodes near 4 tumor 8 Mesenteric lymph nodes 4 8 Superior rectal artery 4 nodes 8 Total 4 8 No Radiotherapy Total X SD n X SD n X SD 4.7 1.80 87 5.8 3.43 135 5.4 3.05 4.7 1.79 87 6.0 2.62 135 5.5 2.44 2.7 1.59 87 4.2 2.87 135 3.7 2.59 12.1 3.0 87 16 5.6 135 14.6 5.3 Comment: - The average number of lymph nodes per 1 patient is14.6 patients (group with preoperative radiotherapy was 12.1 lymph nodes, without radiotherapy was16 lymph nodes). - The average number of lymph nodes near tumor was 5.4 (group with radiotherapy: 4.7, group without radiotherapy: 5.8), mesenteric lymph nodes was 5.5 (group with radiotherapy: 4.7, group without radiotherapy: 6.0), lymph nodes of superior rectal artery was 3.7 (group with radiotherapy: 2.7, group without radiotherapy: 4.2). 11 Table 3:16: The rate of metastasis lymph node classified according to stations. Number of patients Percenta (n) ge % Metastasis rate of 1 LN station 19 14.1 Metastasis rate of 2 LN stations 13 9.6 Metastasis rate of 3 LN stations 10 7.41 Metastasis rate (at least 1 in 3 stations) 42 31.11 Metastatic lymph nodes Comment: The overall rate of lymph node metastasis was 31.11%, in which 7.4% of patients have metastatic lymph nodes in all three stations. Table 3:17: The rate of lymph node metastasis Histology Number of patients (n) Percentage% No metastatic lymph nodes (N0) 93 68.89 From 1-3 positive lymph nodes (N1) 24 17.78 From 4-6 positive lymph nodes (N2a) 3 2.22 More than 6 metastatic nodes (N2b) 15 11.11 135 100.0 Total Comment: The rate of lymph node metastasis is 31.11%, Almost from 1-3 positive lymph nodes (N1: 17.78%). 12 Table 3:18: Lymph node metastasis rate of patients with and without receiving preoperative radiotherapy Radiotherap No y radiotherapy Histology Total p n % n % n % N1/N2 9 18.8 33 37.9 42 31.11 N0 39 81.3 54 62.1 93 68.89 Total 48 100.0 87 100.0 135 100.0 <0.05 Comment: Lymph node metastasis rate of patients treated with preoperative radiotherapy was 18.8% lower than other group (37.9%), the difference is statistically significant with p < 0.05. 3.6. Early Results * The average duration of surgery was 113 minutes (SD 20.87) * The average blood loss was 13.6 ml (SD 12.21) * Complications in operation: 1.4% (intestinal bladder, perforation), no open surgery conversion. * Time using IV or IM algenesthesia: ≤ 2 days. * The time to return of bowel function was: 33.14 ± 4.4 hours. * Postoperative Complications rate was low: 2.8%, 1 case must be operated again due to postoperative bowel obstructions. * The average hospital stay was: 7.38 days (SD 1.82). * There were no deaths due to surgery. 3.7. Long-term results and some factors related to survival time 13 Until 30/06/2012, 116 over 135 patients are alive (85.9%). There is no local recurrence and distant metastasis, 19 patients were died (14.1%). Table 3:28: The median overall survival Mean (months) Median overall survival n X SD 135 33.33 1.00 Comment: The median survival is 33.33 months. 95% CI (31.37 – 35.28) 14 Chart 3.12: The median survival Table 3:29: Overall survival 6 months, 12 months, 24 months, 36 months (Kaplan - Meier) Time Number of patients Percentage% (n) 6 months 116 99.23 12 months 108 95.80 24 months 90 82.11 36 months 36 73.33 15 A number of factors related to survival time: * There is no statisticaly significant difference between group of patients < 60 year old and group > 60 year old (p > 0,05). * The median overall survival in group with lymph node metastasis was 28.42 months lower than group without lymph node metastasis (33.06 months) (no statisticaly significant difference, p > 0.05). * The median overall survival in group with preoperative radiotherapy was 33.34 months higher than those without preoperative radiotherapy (30.74 months), statisticaly significant difference (p < 0.05). * The median overall survival in group with stage III was 28.42 months lower than group with stage II (33.06 months), no statisticaly significant difference (p > 0,05). CHAPTER 4 – DISCUSSION 4.1. General Characteristics * Age and gender: results of the age and sex of this study are similar to other recent studies. * Geography factor (urban or rural areas) do not affect on the study results. 4.2. The clinical and investigations: 4.2.1. Clinical * Time from onset of symptoms to hospital admission was 3.6 ± 1.2 months. The others in Viet Nam was later (4.5 to 6 months). 16 * Symptoms: abdominal pain, tenesmus, accounting for 97.78%. While other authors report mucus stool, difficult defecation. * Digital rectal examination: There are 48 patients with limited motion tumors treated with preoperative radiotherapy. Efron reports accuracy of digital rectal examination is 80%. 4.2.2. Investigation characteristics * The hematological and biochemical tests is normal. This is similar to other studies. * CEA level increased in 30.4% of patients, only 4 patients (2.9%) are higher than 50ng/ml. According to Vietnamese authors, this rate is from 36% to 68.8%. All authors have clear consensus about value of CEA for prognostic and monitoring after surgery. * CTscanner is not high value in evaluation T stage (25% to 80%), and N stage (35% to 70%). Because of this weakness, the number of patients given CTscanner was not many (14.8%). * Magnetic resonance imaging (MRI): According to many studies value of MRI in evaluation T stage is 85% - 95%, and N stage is 84% . Among 135 given MRI, 27.41% of patients with stage III, 72.59% patients with stage II, that reflects the randomization of this study . * Endorectal Ultrasound: Recent studies show that the diagnostic value of endorectal ultrasound is 60% - 90%, N stage is 64% - 83% , especially in sphincter assessment, accuracy up to 90%. However, the number of patients in this study given endorectal ultrasound was still small (18.5%), so we do not comment much on endorectal ultrasound. 4.3. Evaluating lymphadenectomy results of LAPR Lymphadenectomy is a criteria in cancer surgery, it is an important prognostic factor. In laparoscopy, how to lymphadenectomy in cancer principles: 17 rectal filopressure, removal of rectal mesentery, pelvic lymphadenectomy? Rectal filopressure: studies with two-position to tie off (origin of inferior mesenteric artery and division of superior left colon artery) show results of recurrence rate, distant metastatic rate and survival is not different in 2 groups. Today, the cancer surgeon as Bleday at the University of Texas, Garcia-Aguilar in California and Milsom have consensus to tie off at division of superior left colon artery that is enough for LAPR. Our technique also follows this principle. 1982 Heald introduced the concept of Total mesorectal excision (TME) that reduced relapse rate from 15% - 30% to 4%. This is an important change in the surgery history of low rectal cancer. Laparoscopic TME that we do in our study showed the same advantages as described by foreign authors. Pelvic lymphadenectomy is still debate on the world today. Japan is the first one in systematic pelvic lymphadenectomy, but the rate of genitourinary complications such as in the study of Takahashi at Tokyo Institute of Cancer are up to 40%. But the European-American authors such as McFarlane, Heald, Enker conducted research, compared the results between the two groups with and without pelvic lymphadenectomy and concluded that there is no different while complication rate in lymphadenectomy group is up to 45%. We agreed with the European-American authors, pelvic lymphadenectomy only recommend for patients with pelvic lymph node metastasis on preoperative MRI, or suspicion of pelvic lymph node metastases on intraoperative evaluation. 4.3.1. The number of harvested lymph nodes Laparoscopic lymphadenectomy in LAPR has not been emphasized. According to AJCC-2010, the number of harvested lymph nodes must be at least 12 new lymph nodes for evaluating N stage. Among 135 patients with low rectal cancer in this study, the number of harvested lymph nodes are 1977, the average number of lymph nodes per 1 patient is 14.6. (preoperative radiotherapy group is 18 12.1; group without radiotherapy is16). 4.3.2. Metastasis lymph nodes classified according to stations There is a century history of rectal cancer surgery, but maps of lymph node metastasis still have been studied. Galandiuk in 2005, Pirro in 2008 reported 80% of lymph nodes in rectal mesentery. In this study, we obtained an average number of mesorectal lymph nodes was 10.9 (lymph nodes near tumor was 5.4 and mesorectal lymph nodes was 5.5), lymph nodes of superior rectal artery was 3.7. This result is similar to the foreign authors. Lymph node metastasis in rectal cancer also follow the principle of lymphatic metastasis in cancer from the primary tumor to near stations and go further. Our results also follow this principle, Metastasis rate of 1 LN station was 14.1% , 2 stations is 9.6%, 3 stations is only 7.41%, there is no skip metastasis . Overall metastatic rate is 31.11%. Stage N1: 17.78%; N2a: 2.22%; N2b: 11.11%. Almost studies in Viet Nam and on the world analyze overall metastatic rate without detailed analysis on metastasis lymph nodes classified according to stations and stage. How preoperative radiotherapy influenced the rate of lymph node metastasis in low rectal cancer is the subject of major concern in the world cancer conference. The large study in Europe, Japan, the United States show the number of harvested lymph nodes and the rate of lymph node metastasis reduce in patients with preoperative radiotherapy. This study also shows that the the average number of harvested lymph node in preoperative radiotherapy group was 12.1 nodes / patient ( near tumor 4.7, mesenteric lymph nodes 4.7, superior rectal artery 2.7), and lymph node metastasis rate was 18%. The other group was 16 node/patient (near tumor: 5.8 nodes, mesenteric lymph nodes 6.0 nodes; superior rectal artery : 4.2 nodes) and lymph node metastasis rate was 37.9%.
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