Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT00193817 |
| Other study ID # |
TMH 111/IM-2004 |
| Secondary ID |
DAECTC/Projno 5 |
| Status |
Recruiting |
| Phase |
Phase 3
|
| First received |
September 14, 2005 |
| Last updated |
February 6, 2006 |
| Start date |
January 2005 |
| Est. completion date |
December 2015 |
Study information
| Verified date |
July 2005 |
| Source |
Tata Memorial Hospital |
| Contact |
Rajesh C Mistry, MS |
| Phone |
91-22-2417 7000 |
| Email |
mistryrc[@]tmcmail.org |
| Is FDA regulated |
No |
| Health authority |
India: Department of Atomic Energy |
| Study type |
Interventional
|
Clinical Trial Summary
Surgery is the standard treatment for esophageal (food pipe) cancer. Esophageal cancer is
known to spread to the lymph nodes (glands) adjacent to the esophagus. The extent of lymph
nodes that need to be removed along with removal of the esophagus is a controversial topic.
The basic surgery will remain the same i.e., the foodpipe in the chest will be removed and a
new substitute will be created from the stomach and joined to the foodpipe in the neck. This
will involve incisions in the chest, abdomen and neck. We intend to compare two types of
lymphadenectomy (removal of lymph nodes) - the two field lymphadenectomy, whereby the lymph
nodes in the abdomen and the lower half of the chest will be removed and three field
lymphadenectomy, wherein lymph nodes in the abdomen, the whole chest and the lower neck will
be removed. Both these procedures are practised widely worldwide and there is no definite
scientific evidence showing the superiority of either of them. We are conducting this study
to see whether one of these procedures is superior to the other. Seven hundred patients are
expected to participate in this study.
Description:
Three field radical esophagectomy versus two field esophagectomy – a prospective randomized
controlled trial
Background Esophageal cancer is a common problem worldwide and is associated with poor
prognosis. Surgery is the mainstay of treatment and offers the only realistic possibility of
cure and long term survival. Neoadjuvant and adjuvant chemotherapy and radiotherapy have
been tried in addition to surgery and have only marginally impacted on survival. In spite of
advancements in postoperative care and refinements in surgical technique, overall results
with surgery have been disappointing. Moreover studies of neoadjuvant and adjuvant therapy
have been confounded by the lack of a uniform surgical approach and extent of
lymphadenectomy.
The efficacy of prophylactic radical lymph node dissection in surgical treatment of
esophageal cancer has been a topic of major controversy for many years. It has not been
studied in a randomized controlled trial with adequate numbers. Non randomized studies have
been criticized on the basis of selection bias and stage migration. There is presently no
convincing evidence regarding improvement in survival by extensive three field
lymphadenectomy.
Objectives
1. To compare overall survival after three field and two field esophagectomy
2. To compare locoregional recurrence, disease free survival after three field and two
field esophagectomy
3. To compare postoperative morbidity and mortality in the two groups
4. To evaluate short and long term quality of life after the two procedures
Design Prospective randomized controlled trial Setting Tertiary level comprehensive cancer
care centre in Western India. Patients and methods All patients with biopsy proven carcinoma
of the esophagus presenting to our hospital will be considered for the study.
Inclusion criteria
1. Patients with biopsy or cytology proven (squamous or adenocarcinoma) esophageal cancer
(including Siewert’s type I and II CO junction cancers)
2. Patients with staging investigations indicating operability
3. Surgical plan for total transthoracic esophagectomy
Exclusion criteria
1. Patients with low performance status (ECOG score > 1)
2. Past history of malignancy
3. Staging investigations indicating advanced disease
4. Patients medically unfit for surgical resection
5. Patients with pulmonary reserve inadequate to undergo thoracotomy and extensive
mediastinal dissection
6. Patients considered for salvage surgery after definitive chemoradiotherapy
7. Patients unreliable for follow up
8. Patients above the age of 70 years
9. Patients with enlarged supracarinal nodes on CT scan / EUS
10. Grossly enlarged supracarinal lymph nodes seen intraoperatively
11. Patients with Siewert’s type III cancers.
A detailed history including the main complaints and symptoms, symptoms suggestive of
advanced disease or dissemination, comorbid conditions and performance status of the patient
will be recorded on presentation. A confirmed diagnosis of esophageal carcinoma will be
documented in our hospital.
Staging investigations will be standard and will include
1. Computed Tomography (CT) scans in all patients
2. Endoscopic Ultrasonography (EUS) wherever possible
3. Fiberoptic bronchoscopy (all upper and middle third growths and patients with history
of recent voice change).
4. Symptomatic patients will undergo further investigations depending on the symptom.
Patients undergoing neoadjuvant chemotherapy or chemoradiotherapy will not be excluded but
will be one of the stratification criteria for randomization. Patients will be assessed for
operability by a team including two qualified thoracic surgeons and a radiologist. All
patients will undergo routine and special investigations where indicated to assess fitness
for major surgery and anesthesia. The perioperative risk will be assessed by a combination
of the American Society of Anesthesiologists (ASA) grading and a modified risk score
(Annexure 1). Patients with ASA grade I or II and those who have low or intermediate risk
according to the modified risk scoring system will be considered for the trial. Patients
will be explained about the trial and written informed consent will be taken (Annexure 2).
Patients considered operable (either per primum or after neoadjuvant therapy) and fit for
either procedure and who consent for the trial (Eligibility confirmation and randomization
form, annexure 3) will be randomized into two groups.
Randomization Block randomization will be done using a computer generated sheet.
Randomization will be performed intraoperatively after confirming resectability of the
primary tumor and confirming the absence of grossly enlarged supracarinal lymph nodes
Stratification criteria
1. Preoperative T stage (T1&2, T3 and T4)
2. Preoperative N stage (N0, N1)
3. Level of disease (upper, middle and lower third)
4. Neoadjuvant therapy (none, chemotherapy, chemoradiotherapy)
5. Histology (squamous or adenocarcinoma).
All patients considered for the trial will have a proforma filled for pre, intra and
postoperative details (Annexure 4). Preoperative patient preparation would be routine and
identical in both groups and will include chest physiotherapy, deep breathing exercises and
incentive spirometry. Bronchodilators and antibiotics will be used selectively only if
indicated.
Trial schema Patients with esophageal cancer
Staging investigations (CT scan, EUS, FOB) indicating operable disease with surgical plan of
total transthoracic esophagectomy
Investigations for fitness for surgery indicating good risk for surgery STRATIFY
1. Preoperative T stage (T1&2, T3 and T4)
2. Preoperative N stage (N0, N1)
3. Level of disease (upper, middle and lower third)
4. Neoadjuvant therapy (none, chemotherapy, chemoradiotherapy)
5. Histology (squamous or adenocarcinoma)
RANDOMIZE
Three field esophagectomy Two field esophagectomy
All surgeries will be performed under general anesthesia with epidural analgesia. The
surgery will be either performed by or under the direct supervision of consultant thoracic
surgeons with experience in esophageal surgery. Thoracic esophageal mobilization and
mediastinal lymphadenectomy will be done by open thoracotomy or video assisted thoracoscopic
surgery. Lymphadenectomy will be as defined in the consensus conference of the fifth IGSC at
Munich.
Field 1. The abdominal field will include all lymphatic and connective tissues between the
hiatus cranially, the upper border of the pancreas caudally, the splenic hilum to the left
and the hepatoduodenal ligament and right gastric artery to the right.
Field II. This refers to the intrathoracic compartment and is defined as
1. Standard lymphadenectomy: This includes para esophageal lymph nodes, subcarinal lymph
nodes and right and left para bronchial lymph nodes.
2. Extended lymphadenectomy: This includes the standard lymphadenectomy plus the right
apical nodes, right recurrent nerve nodes and the right paratracheal nodes.
3. Total lymphadenectomy: This includes the extended lymphadenectomy plus the left apical
nodes plus the left recurrent nerve and paratracheal nodes.
Field III. This refers to the cervical compartment and includes clearance in the omohyoid
triangle with sparing of the sternocleidomastoid muscle and the internal jugular vein. The
cranial landmark is the cricoid cartilage and the caudal landmark the upper margin of the
clavicle.
Three-field lymphadenectomy: The type of resection will include lymph node clearance of
Fields I and III and a total type Field II lymphadenectomy.
Two field lymphadenectomy: The type of resection will include lymph node clearance of Field
I and any of the types of lymphadenectomy in Field II. Standard mediastinal lymphadenectomy
will be done in all patients; no special effort will be made to dissect the supracarinal
compartment unless grossly enlarged lymph nodes are seen.
Three field lymphadenectomy Two field lymphadenectomy
Operative time, blood loss, blood product replacement and all intraoperative details will be
recorded in the proforma. Patients will be shifted postoperatively to the intensive care
unit (ICU) for observation and subsequently to the recovery or high dependency ward once
stabilized. Postoperative details including period of postoperative ventilation, hemorrhage,
pulmonary and cardiac complications, arrhythmias, thoracic duct leak, anastomotic leak,
wound infection and recurrent laryngeal nerve paresis or palsy will be recorded.
Postoperative complications will be recorded as per Annexure 5. Postoperative mortality will
be defined as 30-day mortality plus death before discharge after surgery.
Patients will be started on oral feeds between the 8th and 10th day in the absence of an
anastomotic leak. The total duration of ICU stay and hospital stay will also be recorded.
Follow up Patients will be followed up four to six monthly for the first three years and
annually thereafter. A detailed history and clinical examination will be done on every
follow up with the quality of speech, swallowing recorded. Patients who had a fixed cord
postoperatively will undergo laryngoscopy to assess recovery of function. Symptomatic
patients will be investigated by upper gastrointestinal endoscopy, CT scan, ultrasound and
haematological and biochemical investigations. Asymptomatic patients will not be routinely
investigated.
Sample size The sample size considering an improvement of survival from 25% to 35% will be
588 patients (289 in each arm). The trial will aim at enrolling 700 patients in order to
adjust for loss to follow up and protocol violations. Interim analyses will be done when ¼
th (103 events) and ½ (206 events) of the estimated events occur. We expect to complete
accrual of patients in seven years.
Data management All collected data will be entered into a statistical software package for
subsequent analysis (SPSS for Windows, Version 11.5)
Main research variables Primary end point Overall survival in the two arms Secondary
endpoints
1. Disease free survival
2. Locoregional recurrence
3. Postoperative morbidity and mortality
4. Quality of life – short and long term
