Summary of the thesis: Research on Treatment of esophageal cancer by right thoracoscopic esophagectomy combined wit laparotomy

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.

HO HUU AN

RES EARC H ON TR EA TMENT O F ESO PHAGEAL C ANC ER

BY RIGHT THO RACOSCOPIC ESOPHAGEC TO 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

PHARMACEUTICAL SCIENCES

Name of supervisor:

1 Associate Professor & Ph D Trieu Trieu Duong

2 Ph D Nguyen The Truong

Re vie we r 1:

Re vie we r 2:

Re vie we r 3:

The thesis will be defened on … date……month… 2019

The thesis can be found in:

1 Nat ional library of Viet Nam

2 Library of 108 Institute of Clinical Medical and Pharmaceutical Sciences

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 McKeown-Akiyama) 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:

1 to describe some clinical and subclinical features of patients with esophageal cancer having been treated by right thoracoscopic esophagectomy combined with laparotomy

2 to review the outcomes of esophageal cancer treatment with right thoracoscopic esophagectomy combined with laparotomy

DISSER TA TIO 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

1 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 2 and T3 are (38%; 95%), (50%; 79%) and (74%; 75%) respect ively 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 0 are of 4.2%, stage I of 14.1%, stage II of 59.2%, stage III of 22.5%, and stage

IV of 0%

2 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, reduct ion 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 DISSER TA TIO N

The dissertation consists of 123 pages, including abstract of 2 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 1 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 1

O VERVIEW 1.1 ANATO MY O F THE ESO PHAGUS - STO MAC H

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 Rel ations

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

investigat ion to assess the invasion of the mediastinum and nodal disease, and detect distant metastases This is considered a good investigat ion 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 det ection are 51% [95% CI, 34%–69%] and 84% (95% CI, 76%–91%) respectively

Ot her 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 t o WHO classificat ion 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

classificat ion proposed by various cancer associations, however, the classificat ions 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 3 factors, including T (primary tumor), N (regional lymph nodes) and M (distant metastasis)

* 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 (composit e 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 mobilizat ion 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 PHAGEC TO 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: 7 – 29 nodes Rate of transfer to open surgery of thoracoscopic phase: 0 - 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 1 3: Complications in the studies

Postope rative

complications

Authors

Smit her n=309

Jakhmola n=48

Kinjo n=34

Kubo n=28 General complications

1.5.2 Vie t 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: 1 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 2 RESEARC H SUBJEC T AND METHO DO

2.1 RESEARC H TIME AND LO C ATIO N

The research was conduct ed at 108 Military Central Hospital from January 2010 to December 2017

2.2 RESEARC H SUBJEC T

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 III

I Patients with ASA ≤ 3, without any contraindication against endotracheal anesthesia

2.2.2 Exclusion criteria

- Patients having undertaken other procedures of esophagetomy

- Patients combined with other malignent pathologies, and those of insufficient patient profile

- Indicate for surgery for stage I-III esophageal cancer

- Indicate for Van Hagen chemoradiotherapy [54]

- Evaluate pathological stages in accordance with AJCC - 2010

- Collect Histological specimens as the golden standard for diagnosis

- Monitor and evaluate early outcomes within 30 days posoperatively Schedule for follow-up visits or telephone to evaluate Long-time outcomes at 3 months, 6 months, 1 year, and 3 years, etc

- Collect data in line with consistently agreeable patient files

2.3.2 Re search chart

2.3.3 Sample size: T he minimal sample size is calculated with an

equat ion of 95% liability The number of patients in the prospective group is 60 patients

2.3.4 Procedures applied in the research

2.3.4.1 Right thoracoscopic esophagectomy

* Patient and surgical equipem ent preparation

* Patient positioning and surgical team location

* Steps of the surgery

- T horacic phase: Right thoracoscopic surgery

Dissect the esophagus and posterior mediastinum

Dissect and mobilize the esophageal part s superior and inferior

to the t umor, lymphadenectomy

Insert a drain in the right pleural cavity

- Abdomino-cervical phase:

Open the abdomen to create a gastric conduit

Dissect the nodal system in the upper abdominal quadrants Creat e the cervical gastroesophageal anastomosis

2.3.5 Evaluation standards

2.3.5.1 AJCC-2010 stage evaluation

2.3.5.2 ASA pre-operative anesthetic classification

chem oradiotherapy

2.3.6 Re search crite ria

2.3.6.1 General inform ation of the patients: Age, gender, pathological

history, time of det ect ion, reasons of admission and clinical symptoms

2.3.6.2 Pre-treatment assessment: Assess tumor location and invasion,

nodal metastasis by preoperative gastroesophageal endoscopy and CT scan, and assess respiratory functions

2.3.6.3 Evaluate pre-operative chem oradiotherapy outcomes

2.3.6.4 Rate and record intraoperative scores: number of t rocars used

during the thoracic phase, surgery durat ion, intraoperative complications, number of nodes dissected

2.3.6.5 Postoperative evaluation param eters

- Early outcomes: T ime at recovery, hospitalization, removal of thoracic, abdominal and anastomosis drains, postoperative mortality, early complications, postoperative histology

- Long-time outcomes: Long-time complications, recurrence, survival time and factors affecting postoperative survival time

2.3.7 Data management and processing

2.3.8 Re search ethics

Chapte r 3 RESULTS 3.1 CO MMO N CHARAC TERISTIC S

- Mean age 55.8 ± 8.3 years old (40 - 76) 100% male

- 13 patients (18.3%) with combined internal diseases 3 patients (4.2%) with previous surgeries, however, most of them had been operated in the lower abdominal quadrants and the extraperitoneal space

3.2 C LINICAL AND SUBCLINICAL PRESEN TA TIO N

- Macroscopy: Fungating pattern comprises most 67.6 % (48/71)

- Microscopy: Squamous cell carcinoma mostly common (97.2%)

3.2.2.2 Respiratory functions: Most patients have normal respiratory funct ions (88.7%), none of them have any severe ventilation disorder 3.2.2.3 CT scan

- Tumor location: 100% t umors in the middle third and lower third of

the esophagus

- Invasion shown in the CT scans: A majority of patients have invasion

to cT2-cT3 comprising 83.1% of which cT3 accounts for 56.3%

- Values for diagnosis of invasion by CT scan:

+ Sensitivity to T1, T2 and T 3 are 38%, 50% and 74% respectively + Specificity to T1, T 2 and T3 are 95%, 79% and 75% respectively + Accuracy for T 1, T2 and T 3 are 85%, 69% and 75% respectively

- Values for diagnosis of m ediastinal nodal m etastases of CT scan:

sensitivity 53%, specificity 46%, accuracy 48%

- Values for diagnosis of abdominal nodal metastases of CT scan:

sensitivity 80%, specificity 85%, accuracy 84%

3.2.2.4 Postoperative pathology

- Microscopy: Squamous cell carcinoma accounts for most 93.0 %

There are 3 patients (4.2%) whose specimens are not observed with any tumor cells following preoperative chemoradiotherapy

mestastatic nodes

Comments: 24 patients (33.8%) with nodal metastases, of whom the

mediastinal nodal metastasis rat e is 23.9%, abdominal nodal metastasis rate is 18.3%

- Nodal m etastasis from pathologylogy: pN0, pN1, pN2 and pN3 rates

are 66,.2%, 21.1%, 11.3 % and 1.4% respect ively Mean number of metastatic nodes is 2.8 ± 2,6 (1-13)

T able 3.2 Cancer stages

Stages

Chemoradi othe rapy -

PT (n=17)

Surgery (n =54)

Total (n =71)

Comment: T he group without any preoperative chemoradiotherapy:

Patients of stage II account for most (61.1%) T he group with preoperat ive chemoradiotherapy: mostly at stages I and II (64.7%) There are 3 patients (17.6%) who are found without any more tumor cells after chemoradiotherapy

3.3 TR EA TMENT O UTCO MES

Comment: There are 23.9% of the patients treated with preoperative

chemoradiotherapy + surgery, 40.9% of the patients only treated with surgery