MINISTRYOFEDUCATIONANDTRAINING MINISTRYOF NATIONAL DEFENCE 108 INSTITUTE OF CLINICAL MEDICAL ANDPHARMACEUTICALSCIENCES HO HUU AN RES EARC H ON TREATMENT O F ESO PHAGEAL CANCER BY RIGHT THO RACOSCOPIC ESOPHAGECTO MY CO MBINED W ITH LAPARO TO MY Spe ciality: Gastrointe stinal surgery Code : 62720125 SUMMARY O F TH E TH ESIS Ha Noi - 2019 THE THESIS WAS COMPLETED AT 108 INSTITUTE OF CLINICAL MEDICAL AND PHARMACEUTICAL SCIENCES Name of supervisor: Associate Professor & Ph D Trieu Trieu Duong Ph D Nguyen The Truong Re viewe r 1: Re viewe r 2: Re viewe r 3: The thesis will be defened on … date……month… 2019 The thesis can be found in: Nat ional library of Viet Nam Library of 108 Institute of Pharmaceutical Sciences Clinical Medical and ABSTRAC T Esophageal cancer is the 4th most common cancerous diseases of the gastrointestinal tract, with increasing incidence rates In 2005 there were 497,700 new cases and the rate may increase up to 140% in 2025 It also causes high death rate with 416,500 deaths in the US in 2005 Treatment of esophageal cancer is a multimodality, including surgery, chemotherapy and radiotherapy, of which surgery plays the most important role Transthoracic esophagectomy (TTE) (by Ivor Lewis or McKeownAkiyama) or trans-hiatal esophagectomy (THE) (by B Orringer) are the most common surgeries to t reat esophageal cancer However, convetional open surgery has high rates of complications of 23 - 40%, with 1.2 – 8.8% of mortality rate With the fast advances of minimally invasive surgery in almost the last decades, minimally invasive esophagectomy has been applied and quickly advanced with such benefits as reduced complications, especially pulmonary comlications, and shortened hospitalization and recuded costs for patients Some recent research reports have proven the safety and feasibility of the surgery However, there are still controversies about the safety, feasibility and outcomes of cancer treatment study of minimally invasive surgery in the treatment of esophageal cancer In Viet Nam, minimally invasive surgery for treating esophageal cancer has been implemented since 2003 at Big centers such as Cho Ray Hospital, Viet Duc Hospital and 108 Military Central Hospital However, there has not been any research with sufficient long-term outcome review of the approach With the above-mentioned matters, we would like to study the topic, “Research on Treatment of esophageal cancer by right thoracoscopic esophagectomy combined wit laparotomy” with the objectives as follows: to describe some clinical and subclinical features of patients with esophageal cancer having been treated by right thoracoscopic esophagectomy combined with laparotomy to review the outcomes of esophageal cancer treatment with right thoracoscopic esophagectomy combined with laparotomy DISSERTATIO N The research was conducted on 71 patients with esophageal cancer treated with right thoracoscopic surgery combined with laparotomy at the 108 Military Central Hospital from January 2010 to December 2017 Some clinical and subclinical features: Common symptoms include dysphagia (81,7%) and weight loss (80,3%) Adenocarcinoma is most common comprising 67.6% Squamous cell carcinoma comprises 97.2% The tumor in the middle third of esophagus are 57.1% and in t he lower third 47.9% T he sensitivity and specificity of CT scans t o T1, T and T3 are (38%; 95%), (50%; 79%) and (74%; 75%) respectively The rate of nodal metastases is 33.8% (24/71) T he avrage number of metastatic nodes are 2.8 ± 2.6 (1-13) Stage are of 4.2%, stage I of 14.1%, stage II of 59.2%, stage III of 22.5%, and stage IV of 0% Outcomes of surgeries - Intraoperative outcomes: Mean surgical time 193.9 ± 49.3 minutes, average number of node removed is 10.1 ± 8.6 The rate changing to open technique is 1.4% Complications are of 7.0% - Early complications include pneumonia of 12.9%, respiratory distress of 7.1%, anastomotic leaks of 11.4%, chylothorax of 4.3%, and mortality of 0% - Long-term outcomes: Long-term monitoring 21.7 ± 19.4 months long T he rate of postoperative complications is 33.3%, delayed complication rate is 24.6% Overall survival rate is 45.7 months (95% CI:35.9-55.4) The overall survival rate after one, two, three and four years are 79.7%, 62.3%, 52.3%, and 43.6% respectively As a result, the study has made some new contributions, confirmed the safety, feasibility, efficacy, reduction of complications and ensured the oncological principles of the right thoracoscopic esophagectomy combined with laparotomy for treatment of esophageal cancer TH E S TRUC TUR E O F TH E DISSERTATIO N The dissertation consists of 123 pages, including abstract of pages, overview of 36 pages, study subject s and method of 20 pages, study results of 26 pages, discussion of 39 pages and conclusion of page T wo research with 40 t ables, 07 charts and 22 pictures 133 reference materials, including 13 in Vietnamese language and 120 in foreign languages Chapte r O VERVIEW 1.1 ANATO MY O F THE ESO PHAGUS - STO MACH 1.1.1 Shape 1.1.2 Structure The esophageal wall is composed of four layers from outermost to innermost, including the outermost adventit ia, muscularis propia, submucosa and mucosa 1.1.3 Relations 1.1.4 Blood supply and innervation The esophagus has art erial supply, including inferior thyroid artery, bronchial branch of aortic artery, left gastric artery (55%) and left inferior phrenic artery Vagus nerve (nerve X) supplies nerves to esophagus The upper segment of the esophagus is coordinated by the branches of the recurrent laryngeal nerve 1.1.5 Lymphatics Below the esophageal mucosa is a lymphatic drainage system of mainly longitudinal vessels The lymphatic drainage system drains into bigger lymph nodes and form the surficial lymphatic plexus and then connect to the lymph nodes along the esophagus 1.1.6 Gastric arte ries: The branches supplying blood to the stomach which originate from the celiac trunk include branches for the lesser gastric curvature, fundic and cardiac part s of the stomach, and short gastric arteries 1.2 DIAGNOS IS 1.2.1 Clinical Common symptoms include dysphagia, vomiting, pain in the retrosternal area, hoarseness, weight loss, malnourishment and tylosis 1.2.2 Subclinical: Pre-treatment diagnosis is highly significant for esophageal cancerous diseases Ho wever, there are still a lot of challenges for pre-operative diagnosis Therefore, in order to have an accurat e diagnosis, not only one approach but various approaches should be incoporated 1.2.2.1 Endoscope: Endoscope combined with biopsy may have the sensitivity up to 96% Advantages: Low cost, widely applicable even at lower levels of the health services; noninvasive, may apply for treatment interventions such as mucosa or submucosa removal for very early stages 1.2.2.2 Endoscopic ultrasound: is a significant subclinical approach to assess tumor invasion especially the invasion of the esophageal wall 1.2.2.3 Computed tomography scan: is an important subclinical investigation to assess the invasion of the mediastinum and nodal disease, and detect distant metastases This is considered a good investigation for preoperatively staging esophageal cancer 1.2.2.4 Magnetic resonance imaging (MRI) scan: With technological advances, MRI scans combined between T2W and DWI sequences have been reported with detection rates in assessing tumor invasion of T1 33%, T2 58%, T3 96% and T4 100% 1.2.2.5 Positron emission tomography (PET/CT) scan: Multiple analytic studies have shown the sensitivity and specificity of FD-PET for local metastatic lymph node detection are 51% [95% CI, 34%–69%] and 84% (95% CI, 76%–91%) respectively Other studies have shown t hat FDG-PET has higher sensitivity for determination of distant metastases than other methods such as CT scan, ultrasound and SPECT Luketich found that FDG-PET has the sensitivity of 88% (7/8) and the specificity of 93% (25/27) for distant metastasis detection 1.3 HISTO PATHO LO GY AND STAGES 1.3.1 Histopathology 1.3.1.1 Macroscopy: Esophageal cancer has three common patterns: fungating comprises more than 60%, ulcerative (20 - 30%), infiltrating is rare about 10% 1.2.1.2 Microscopy: According to WHO classification in 1977, there are: squamous cell carcinoma (more than 90%), adenocarcinoma (~ 9%), melanoma, Sarcoma (rare, about l%) 1.3.2 Stage classification: There are many different methods of classification proposed by various cancer associations, however, the classifications by the Union for International Cancer Control (UICC) and American Joint Committee on Cancer (AJCC) have been widely applied The staging of esophageal cancer is based on factors, including T (primary tumor), N (regional lymph nodes) and M (distant metastasis) 1.4 TREATMENT 1.4.1 Flowchart of treatment of esophage al cance r 1.4.2 Surgery Such methods as transthoracic esophagectomy, Ivor-Lewis (via the thorax) and the 3-incision approach is the most common method in countries in North America, whilst transthoracic esophagectomy and extensive nodal dissect ion (the three-dimensional t echnique) is widely employed in Asian countries such as Japan and South Korea * Akiyama method in esophagectomy: in 1971, Akiyama introduced the procedure: firstly, open and expose the chest cavity for esophagectomy, then open the abdomen to create a gastric conduit, followed by opening the neck to create an esophagogastric anastomosis The procedure is performed in three approaches: thoracic, abdominal and left neck incisions - Advantages: Extensive nodal dissect ion in the mediastinum, abdomen and neck; high resection of the esophagus ensures safet y of the resection surface, cervical anastomosis is easy for anastomotic leak revision, if any, and lowers the rate of reflux - Disadvantages: cervical anastomosis may increase the risk of postoperative anastomotic leak and stricture 1.4.3 Esophageal substitute Esophageal substitutes are of two types: auto-transplanted tissues, including stomach, jejunum or colon, and synthesis (composite combined with collagen, plastic tubes) Stomach is the ideal esophageal replacement for alimentary reconstruction after esophagectomy, because of its sufficient vascular supply, sufficient length for mobilization for creating either thoracic or cervical anastomosis, and only one anastomosis required so shorter operation time T he main disadvantage of gastric conduit is inflammatory gastroesophageal stricture developed from acid or bile reflux 1.4.4 Minimally invasive surgery Minimally invasive surgery in treating esophageal cancer has been widely applied with the benefits of small incisions, less intraoperative blood loss, less postoperative complications, shortened intensive care and hospitalization and better postoperative respiratory recovery 1.4.5 Nodal disse ction in surgery for e sophage al cance r In 1994, at t he International Society for Diseases of the Esophagus (ISDE) held in Munich, Germany, a concept of the area for lymphadenectomy T he term “2-level lymphadenectomy” is accordingly used for abdominal and mediastinal nodal dissection whilst the term “3-level lymphadenectomy” is used for abdominal, mediastinal and cervical nodal dissection 1.4.6 Supportive treatment 1.4.6.1 Radiotherapy 1.4.6.2 Chemotherapy 1.4.6.3 Chemoradiotherapy 1.5 REVIEW O F MINIMALLY INVASIVE ESO PHAGECTO MY O UTCO MES 1.5.1 Internationally In 1992, Dallemagne B et al described the first esophagectomy using both thoracoscopy and laparoscopy with gastrict conduit and cervical anastomosis for treating esophageal cancer There have been many other studies proving that thoracoscopic esophagectomy is a safe and feasible procedure for treating esophageal cancer: Duration of thoracoscopic phase: 90- 281 minutes Average blood loss: 200 - 536 ml Number of nodes dissected in thoracoscopic phase: – 29 nodes Rate of transfer to open surgery of thoracoscopic phase: - 20% The studies have also shown the outcomes of right thoracotomy approach in esophagectomy are very encouraging with reduced postoperative complication rates, especially respiratory complications T able 3: Complications in the studies Postope rative Authors complications Smit her Jakhmola Kinjo Kubo n=309 n=48 n=34 n=28 General complications 62% ? 58% ? (%) Respiratory 35.4% 38% 17.8% complications (%) Thoracic conduit leaks 2.1 % 10.7% (%) Recurrent laryngeal ? ? 25% nerve injury Anastomosis leak (%) 5.5% 6.3% 8.8% 3.5% Hospitalization 13 ? 32 ? Mortality 2.3% 6.3% 0 1.5.2 Viet Nam T he studies of Minimally invasive surgery in treating esophageal cancer by Nguyễn Minh Hải (2003), Triệu T riều Dương (2003), Phạm Đức Huấn (2006), Lê Lộc (2017) with sample size from 20 - 150 patients resulted in: Average operation durat ion: 330 - 395 minutes Average ICU care time: day Postoperative complications: 10 - 20% T he authors have also concluded that thoracoscopic esophagectomy has wider operating field and better vision, is easier to control bleeding and can be safely performed at medical centers where there are good anesthetic and recovery facilities and competent Minimally invasive surgeons In addition, mediastinal lymphadenectomy can be performed during the Minimally invasive surgeries on candidates for esophagectomy, but for those contraindicated for esophagectomy due t o extensive tumor invasion and metastasis, thoracoscopic surgery also assists in more accurate determination of esophageal cancer stages to avoid unnecessary thoracic opening Chapter RESEARC H SUBJECT AND METHO DO 2.1 RESEARC H TIME AND LO CATIO N The research was conducted at 108 Military Central Hospital from January 2010 to December 2017 2.2 RESEARC H SUBJECT 2.2.1 Selection crite ria - Patients diagnosed with esophageal cancer, having undertaken right thoracoscopic esophagectomy combined with laparotomy - Patients diagnosed with t horacic segment esophageal cancer stages IIII 14 3.3.1 Outcome s of pre operative chemoradiotherapy - Assess tumor invasion before and after preoperative chemoradiotherapy:  The rate of reduced invasion cT after chemoradiotherapy is 66.7% (2/3) patients  The rate of reduced invasion of cT3 after chemoradiotherapy of is 83.3% (10/12) patients  The rate of reduced invasion of cT4 after chemoradiotherapy is 100% (2/2) patients - Evaluate histological response of the tumor after preoperative chemoradiotherapy according to Ryan et al: There are patients (17.6%) with full response, 8/17 (47.1%) patients with average response, 23.5% with limited response and patients (11.8%) without any response to preoperative chemoradiotherapy 3.3.2 Intraope rative outcomes One out of 71 patients is transferred to open surgery therefore we not include this one in the outcomes of Minimally invasive surgery - Quantity of trocars (thoracic phase): There are 53 patients (75.7%) who used trocars, 17 patients (24.3%) who used trocars - Average surgery duration 193.9 ± 49.3 minutes, of which the time for thoracic phase is 74.8 ± 29.5 minutes There is no surgery time difference between the groups with and without preoperative chemoradiotherapy (p>0.05, t test) - Surgical complications: The rate of general complications 7.0%, including patient (1.4%) with bleeding, patients (2.8%) with thoracic tubes, patient (1.4%) with tracheal injury and patient (1.4%) with pulmonary tissue damage, patient (1.4%) t ransferred to open surgery There is no difference in complication rates between between the groups with and without preoperative chemoradiotherapy - T otal mean nodes dissect ed is 10.1± 8.6, with the biggest number of 40 nodes T he mean mediastinal nodes dissect ed is 5.5± 5.5, with the biggest number of 33 nodes T he mean abdominal nodes dissect ed is 4.5 ± 4.6 Total mean nodes dissected in the prospective group is higher 15 than that in the retrospective group with statistical significance (12.0 ± 9.4 vs 7.4 ± 6.7, p < 0.05) 3.3.3 Early outcome s - Early complications: Rate of pneumonia is 12.9%, respiratory distress 7.1%, pleural effusion 7.1%, anastomosis leak 11.4%, chylothorax 4.3%, bleeding 2.9%, recurrent nerve injury 18.6% No mortality within the first 30 days postoperatively There is no difference in the rates of postoperative complications between the groups with and without preoperative chemoradiotherapy (p > 0.05) T able 4: T ime for ICU, drain removal and postoperative care (n=70) Shortest Result Mean Longest ICU care (day) Thoracic drain removal (day) Abdominal drain removal (day) Cervical drain removal (day) Postop care (day) 1.4 ± 1.6 -8 6.5 ± 2.0 - 14 6.1 ± 1.7 - 14 10.3 ± 5.6 – 30 16.4 ± 6.2 - 40 3.3.4 Long - time outcome s and some relate d factors 70 patients are successful with Minimally invasive surgery, however, during the distant monitoring patient has gone missing This patient is not evaluated for long-time outcomes For cum survival time, it is considered still alive (according to Kaplan Meier method) - Mean monitoring time: 21.7 ± 19.4 months - Distant complications: The rate of anastomosis stricture monitored for months is 23.2% (16/69), recurrent nerve injury 15.9% (11/69), 1.4% patient with intestinal obstruction - Immediate and distant recurrence: T he total rate of postoperative recurrence is 33.3%, of which there is 10.1% of immediate recurrence , 16 including recurred cervical nodes of 4.3%, mediastinal and abdominal nodes of 5.8%, no patient with any recurred anastomosis T he rate of distant recurrence is 24.6%, of which the most common location is pulmonary recurrence of 7.2% T able 3.5 Cum survival Monitoring time Characte ristics year years years years Cum survival 79.7% 62.3% 52.3% 43.6% (CI: 95%, (CI:95%, (CI:95%, (CI:95%, 67.5-87.7) 47.5-74.0) 36.2-66.2) 26.7-59.4) Mean cum 45.7 months (CI:95%, 35.9- 55.4) survival Mean 21.7± 19.4 months (1.9 – 81.8) monitoring time Comment: Mean cum survival 45.7 months (CI:95%, 35.9- 55.4) T he rates of first, second, third and fourth year survival are 79.7%, 62.3%, 52.3%, and 43.6% respectively Chart 3.1 Survival functions in accordance with invasion level 17 Comment: Survival functions between different levels of invasion are different, and the difference is statistically significant with χ -= 11.92, p=0.0179