Double-Arm, Randomized Study of Botulinum Toxin Injection as a Pyloric Drainage Procedure for Minimally Invasive Esophagectomy (Phase II)
Phase: PHASE2
Conditions: Esophageal Carcinoma
Sponsor: Roswell Park Cancer Institute

 
 
 
Official Title: Double-arm, Randomized Study of Botulinum Toxin Injection as a Pyloric 
Drainage Procedure for Minimally Invasive Esophagectomy (Phase II) 
 
NCT#   NCT02965976 
 
Document Date:   12/3/2021 
 

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TITLE: Double-arm, Randomized Study of Botulinum Toxin Injection as a Pyloric 
Drainage Procedure for Minimally Invasive Esophagectomy (Phase II)
Roswell Park Cancer Institute
Study Number:
I 283516
Initial Date:
Amendment #1:
Amendment#2: 
Amendment#3:
Amendment#4:
Amendment#5:
Amendment #6: 
Amendment #7  
10 June 2016
28 October 2016
11 August 2017
16 April 2018
06 September 2018
03 February 2020 
13 March 2021
3 December 2021
Principal Investigator:
Moshim Kukar, MD
Roswell Park Cancer Institute
Elm & Carlton Streets
Buffalo, New York 14263
716-845-5807
Moshim.Kukar@RoswellPark.org
Sponsor:
Roswell Park Cancer Institute
Funding:
Roswell Park Alliance Foundation and NCI 
Grant P30 CA016056
Confidentiality Statement
Any and all information presented in this document shall be treated as confidential and 
shall remain the exclusive property of the party (ies) mentioned above. The use of such 
confidential information must be restricted to the recipient for the agreed purpose and 
must not be disclosed, published, or otherwise communicated to any unauthorized 
persons, for any reason, in any form whatsoever without the prior written consent of the 
party (ies) above.
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SYNOPSIS
Title / Phase
Double-arm, Randomized Study of Botulinum Toxin Injection as a Pyloric 
Drainage Procedure for Minimally Invasive Esophagectomy (Phase II)
Roswell Park Cancer Institute 
Study Number
I 283516
Roswell Park Cancer Institute 
Investigator
Moshim Kukar, MD
Sponsor
Roswell Park Cancer Institute
Funding
Roswell Park Alliance Foundation and NCI Grant P30 CA016056
Study Drug(s)
N/A
Objectives
Primary:

Determine if intra-pyloric botulinum toxin injection (Botox©) 
during a minimally invasive esophagectomy decreases 
postoperative occurrence of delayed gastric emptying.
Secondary:

Determine if intra-pyloric botulinum toxin injection during a 
minimally invasive esophagectomy:
o
Reduces the number of repeat procedures for delayed 
gastric emptying within 90 days, 
o
Decreases time to oral intake meeting 100% of nutritional 
requirements,
o
Reduces the incidence of pulmonary complications 
directly related to delayed gastric emptying,
o
Reduces hospital length of stay related to delayed gastric 
emptying and, 
o
Increases patient quality of life.
Study Design
Double-arm, randomized, Phase II study
Target Accrual and Study 
Duration
A maximum of 50 evaluable patients at RPCI will be enrolled. Accrual is 
expected to take up to 6 years. Study participants will be followed for data 
collection for 90 days (routine post-esophagectomy follow-up care and 
surveillance, per standard of care). Data will be collected for 90 days on 
each patient.
Study Procedures
Medical History, Pre-Existing Conditions (including smoking status and 
diabetes): Baseline
Disease Evaluation (Multidisciplinary evaluation and neoadjuvant therapy 
for esophageal carcinoma): Baseline
Hematology, Chemistry: Baseline, Postoperative course
Performance Status: Baseline
Physical Examination (including neurological examination, vital signs, 
and body weight): Baseline, Inpatient and Outpatient Postoperative Course
Electrocardiogram, Chest x-ray, and/or Pulmonary Function tests: At 
baseline, if clinically indicated.
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Pregnancy test (urine): Baseline
Gastrografin swallow or CT esophagram: Surgery to Discharge
Nuclear Medicine Emptying Study: Post Op Visit 2 (+/- 14 days)
Medical and Clinical Evaluation of Delayed Gastric Emptying: 
Inpatient and Outpatient Postoperative Course
Clinical Events of Interest and Adverse Events: During surgical 
procedure, Inpatient and Outpatient Postoperative Course
Nutrition Evaluation: At baseline, if indicated and, Inpatient and 
Outpatient Postoperative Course
EORTC QLQ OES18 Questionnaire: Outpatient postoperative course
Statistical Analysis
Sample Size Determination: The sample size justification is based on the 
primary analysis. We consider a study design with a total sample of n=50 
patients (randomly assigned in a 1:1 fashion to the Botox and non-Botox 
treatment arms) and an interim analysis at n1=30. The performance of this 
study design and decision rules (described in the primary analysis) was 
assessed via simulation study.
Randomization: Patients will be randomized in a 1:1 fashion to the Botox 
and non-Botox treatment arms using a permuted block design. The 
randomization list will be developed by the Department of Biostatistics and 
Bioinformatics.
Primary and Secondary Analyses:
Primary Analysis: A recent study demonstrated that patients that received 
Botox had a delayed gastric emptying rate of approximately 30% as 
compared to a complication rate in historical controls of 70% in patients 
that did not receive botulinum toxin (Botox) (1). A retrospective review of 
patients undergoing minimally invasive esophagectomy at Roswell Park 
Cancer Institute indicates that the rate of postoperative delayed gastric 
emptying is even lower. Therefore, the primary objective is to determine if 
intra-pyloric botulinum toxin injection during a minimally invasive 
esophagectomy decreases postoperative occurrence of delayed gastric 
emptying. The primary outcome is delayed gastric emptying (assessed 
radiographically by nuclear medicine emptying study) which is treated as a 
dichotomous variable.
Patients will be stratified by receipt of neoadjuvant chemoradiotherapy, 
smoking status, and diabetes; and randomized in a 1:1 to the botulinum and 
non-botulinum treatment arms. The primary objective will be assessed 
using the intent-to-treat principle and a one-sided Cochran-Mantel-
Haenszel (CMH) s test about the following hypotheses:
,
𝐻0:𝜃≥1 
𝐻𝐴:θ < 1
where θ is the common odds ratio (COR) for the odds of delayed gastric 
emptying rates for the botulinum versus non-botulinum treatment arms. A 
one-sided test is performed as the rate of delayed gastric emptying is 
expected to decrease in the botulinum arm over the non-botulinum arm; that 
is we expect θ < 1.
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The analysis will proceed in two stages using an O’Brien-Fleming alpha 
spending function. An interim analysis will be conducted after n1=30 patients 
have completed treatment and the final analysis will be conducted after n=50 
patients have completed treatment. The following decision rules will be 
utilized at each analysis:
Analysis
Decision Rule
Interim

If p-value ≤ 0.011396, then reject H0 and stop 
due to superiority.

If 
, then stop due to inferiority.
θ > 1

Otherwise enroll n2=20 patients.
Final

Reject H0 if p-value ≤ 0.046533
Secondary Analysis: The secondary outcomes include additional postop 
procedures, clinically assessed delayed gastric emptying (days to resumption 
of oral feeding, EORTC QLQ-30 QoL scores, and clinical symptoms of 
regurgitation, vomiting, and aspiration), delayed gastric emptying assessed 
by the gastrografin swallow exam or CT esophagram, pulmonary 
complications (aspiration, respiratory failure requiring reintubation, 
pneumonia within 3 months of surgery), and hospital length of stay. All 
variables will be reported by treatment arm using the appropriate descriptive 
statistics and graphical summaries.
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INVESTIGATOR STUDY ELIGIBILITY VERIFICATION FORM
INCLUSION CRITERIA
Participant Name: ___________________________________________________
Medical Record No.: _________________________________________________
Title: Double-arm, Randomized Study of Botulinum Toxin Injection as a Pyloric Drainage 
Procedure for Minimally Invasive Esophagectomy (Phase II) 
INCLUSION CRITERIA
Yes
No
N/A
All answers must be “Yes” or “N/A” for participant enrollment.
Date
1.
Esophageal carcinoma, undergoing minimally invasive esophagectomy 
with intrathoracic anastomosis.
2.
Age ≥ 18 years of age.
3.
Have an ECOG Performance Status ≤ 2. Refer to Appendix A.
4.
Participant or legal representative must understand the investigational 
nature of this study and sign an Independent Ethics 
Committee/Institutional Review Board approved written informed 
consent form prior to receiving any study related procedure.
Investigator Signature: ___________________________________
Date: ___________
Printed Name of Investigator: __________________________________________________
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INVESTIGATOR STUDY ELIGIBILITY VERIFICATION FORM
EXCLUSION CRITERIA
Participant Name: ___________________________________________________
Medical Record No.: _________________________________________________
Title: Double-arm, Randomized Study of Botulinum Toxin Injection as a Pyloric Drainage 
Procedure for Minimally Invasive Esophagectomy (Phase II)
EXCLUSION CRITERIA
Yes
No
N/A
All answers must be “No” or “N/A” for participant enrollment.
Date
1.
Patients who have a history of gastrointestinal dysmotility or 
functional gastroparesis, including diabetic gastroparesis, central 
and peripheral nervous system disorders, renal failure, medication 
side effects, including chronic dependence of promotility agents, 
anticholinergic antispasmodic agents, or chronic narcotic use over 
2 years due to non-cancer causes. Refer to Appendix B for a list of 
pharmacologic agents.
2.
Patients who have a history of previous gastric or duodenal surgery.
3.
Patients who have a history of duodenal ulcer or duodenal fibrosis.
4.
Uncontrolled intercurrent illness including, but not limited to, ongoing 
or active infection, symptomatic congestive heart failure, unstable 
angina pectoris, cardiac arrhythmia, or psychiatric illness/social 
situations that would limit compliance with study requirements.
5.
Allergy to botulinum toxin, and or egg
6.
Pregnant or nursing female participants.
7.
Unwilling or unable to follow protocol requirements.
8.
Any condition which in the Investigator’s opinion deems the participant 
an unsuitable candidate for study participation.
Participant meets all entry criteria:
  Yes
  No
If “NO”, do not enroll participant in study.
Investigator Signature: ___________________________________
Date: __________
Printed Name of Investigator: _________________________________________________
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TABLE OF CONTENTS
1
Background ............................................................................................................................11
1.1
Minimally Invasive Esophagectomy for Esophageal Carcinoma.......................................11
1.2
Risks and/or Benefits..........................................................................................................12
2
Rationale.................................................................................................................................13
3
Objectives...............................................................................................................................13
3.1
Primary Objective...............................................................................................................13
3.2
Secondary Objectives .........................................................................................................14
4
Methodology ..........................................................................................................................14
4.1
Study Design.......................................................................................................................14
4.2
Target Accrual and Study Duration....................................................................................18
5
Participant Selection...............................................................................................................19
5.1
Inclusion Criteria ................................................................................................................19
5.2
Exclusion Criteria ...............................................................................................................19
5.3
Inclusion of Women and Minorities...................................................................................20
6
Study Procedures....................................................................................................................20
6.1
Participant Randomization and Registration ......................................................................20
6.2
Baseline Evaluations...........................................................................................................20
6.3
Treatment............................................................................................................................21
6.4
Inpatient Postoperative Follow-Up Evaluations.................................................................22
6.5
Criteria for Retreatment......................................................................................................23
6.6
Outpatient Postoperative Follow-Up Visits........................................................................23
6.7
End of Study Visit ..............................................................................................................25
6.8
Compliance.........................................................................................................................29
7
Safety Evaluation ...................................................................................................................29
7.1
Clinical Events of Interest ..................................................................................................29
7.2
Serious Adverse Events ......................................................................................................32
7.2.1
Definition ........................................................................................................................32
7.2.2
Reporting Serious Adverse Events .................................................................................33
7.3
Follow-Up for Serious Adverse Events..............................................................................33
7.4
Unanticipated Problems......................................................................................................33
7.4.1
Definition ........................................................................................................................33
7.4.2
Reporting Unanticipated Problems .................................................................................33
8
Data and Safety Monitoring ...................................................................................................34
9
Statistical Methodology..........................................................................................................34
9.1
Sample Size Determination ................................................................................................34
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9.2
Randomization....................................................................................................................34
9.3
Demographics and Baseline Characteristics.......................................................................35
9.4
Primary and Secondary Analyses .......................................................................................35
9.4.1
Serious Adverse Events ..................................................................................................36
9.5
Interim Analysis and Criteria for Early Termination of the Study.....................................36
10
Ethical and Regulatory Standards.......................................................................................37
10.1
Ethical Principles................................................................................................................37
10.2
Informed Consent ...............................................................................................................37
11
Study Responsibilities ........................................................................................................38
11.1
Data Collection ...................................................................................................................38
11.2
Maintenance of Study Documents......................................................................................38
12
Administrative Rules ..........................................................................................................38
12.1
Revisions to the Protocol....................................................................................................38
12.2
Termination of the Study....................................................................................................38
12.3
Confidentiality ....................................................................................................................38
13
Appendices .........................................................................................................................39
14
References...........................................................................................................................45
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IN-TEXT TABLES
Table 1
50% Gastric Emptying Times and Definitions: ..........................................................17
Table 2
Schedule of Procedures and Observations ..................................................................26
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APPENDICES
Appendix A
ECOG Performance Status Scores
40
Appendix B
Ineligible Pharmacologic Agents.........................................................................41
Appendix C
Nuclear Medicine Questionnaire .........................................................................42
Appendix D
EORTC QLQ- OES18 .........................................................................................43
Appendix E
Pre-Procedure Instruction Handout for Patients: .................................................44
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1
BACKGROUND
1.1
Minimally Invasive Esophagectomy for Esophageal Carcinoma
Esophageal carcinoma is the 7th most common cause of death from cancer in men in the United 
States (U.S.). An estimated 16,910 new cases will be diagnosed in the U.S.in 2016, resulting in 
15,690 deaths (2). Multimodality treatment for esophageal carcinoma includes chemotherapy, 
radiation, and surgery in the form of esophagectomy. During an esophagectomy, a majority of the 
esophagus is resected, and the stomach is narrowed to form a tube, creating a “gastric conduit” 
that is then relocated from the abdominal cavity into the thoracic cavity. Because both vagus nerves 
are resected with the specimen, it is theorized that patients may develop gastric dysmotility and 
pylorospasm, with resulting delayed gastric emptying or gastric outlet obstruction. These are both 
major complications, as they may lead to aspiration and pneumonia, inability to tolerate oral intake 
and maintain adequate nutrition, and the need for additional procedures.
One of the major controversial issues currently is how to prevent delayed gastric emptying. Several 
methods have been implemented to improve gastric emptying during open esophagectomy, with 
inconclusive results. In the minimally invasive setting, surgeons are utilizing intra-pyloric 
botulinum toxin injection to prevent pyloric spasm and thus minimize gastric outlet obstruction. 
Retrospective studies comparing botulinum toxin to historical controls demonstrate inconclusive 
results regarding the ability of botulinum toxin to decrease rates of delayed gastric emptying. This 
study aims to test whether it is necessary to use botulinum toxin as a pyloric drainage procedure 
during minimally invasive esophagectomy. We hypothesize that it is not effective in preventing 
delayed gastric emptying, and that performing botulinum injection adds cost and time to an already 
lengthy procedure, without decreasing the procedure complication rate or benefitting patient 
outcomes.
Improving gastric emptying is crucial to not only maintaining independent nutrition, but also in 
preventing devastating pulmonary complications including aspiration and subsequent pneumonia. 
In the era of open esophagectomy, several types of drainage procedures were employed during 
esophagectomy in an attempt to prevent gastric outlet obstruction. These include pyloroplasty 
(full-thickness longitudinal incision closed transversely), pyloromyotomy (incision through 
muscle only, preserving integrity of mucosal layer), and finger fracture (manual pressure on the 
pylorus, causing muscle disruption). Other surgeons elected not to perform any type of drainage 
procedure. Advocates of the “no drainage” procedure believed that surgical manipulation of the 
pylorus during drainage procedures leads to short-term inflammation and edema, which may cause 
gastric outlet obstruction despite that this procedure is designed to prevent such occurrence. In 
addition, pyloric drainage procedures may lead to dumping syndrome, bile reflux, or leak at the 
pyloroplasty site, leading to intra-abdominal or intra-thoracic sepsis and even death (3). Possible 
long-term side effects include scar or stricture formation. Alternatively, no drainage procedure 
may cause gastric outlet obstruction, leading to inability to tolerate oral diet, aspiration, and 
pneumonia. Whether or not to perform a pyloric drainage procedure is controversial.
With newer minimally invasive esophagectomy techniques, many surgeons omitted drainage 
procedures, as they are technically challenging to perform minimally invasively. Other surgeons 
use botulinum injection at the pylorus as a minimally invasive pyloric drainage procedure, with 
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the theory this relaxes the muscle without causing inflammation, edema, or risk of leak. 
Intraoperative botulism toxin injection is safe and simple to perform, without significantly adding 
to the total operative time. It does however add significant cost to the procedure, approximately 
$1,000 per treatment (1). Botulinum toxin injection into the pyloric sphincter has a pharmacologic 
duration of three to five months (4).
There is much controversy as to the optimal surgical management of the pylorus. A recent review 
of studies performed on this topic in the past ten years concluded that pyloric drainage procedures 
were associated with a non-significant trend towards delayed gastric emptying and biliary reflux, 
while not affecting the incidence of dumping (5). Two other meta-analyses supported pyloric 
drainage, showing decreased rates of gastric outlet obstruction and improved gastric emptying (6, 
7). These meta-analyses reviewed randomized controlled trials published between 1984-2002, 
prior to minimally invasive technique and botulinum use. Over the past ten years significant 
changes were made to the way esophagectomies are performed, and these studies do not apply to 
our patient population today. Major changes in technique include the transition to minimally 
invasive technique, stapled technique for anastomosis and tissue transection, and tubularization of 
the stomach conduit as opposed to use of the whole stomach. With minimally invasive techniques, 
surgical pyloric drainage procedures are difficult to perform, and frequently omitted. When the 
whole stomach is used as a conduit, the conduit becomes redundant, and such a large reservoir is 
conducive to gastric stasis. With a narrower conduit, surgeons advocate drainage procedure is 
unnecessary because the occurrence of redundancy and stasis is lower. Lastly, these studies were 
published prior to the use of botulinum toxin.
Three retrospective reviews comparing botulinum to pyloric drainage procedures versus no 
drainage procedure during open esophagectomy have found a significant benefit of botulinum in 
preventing gastric outlet obstruction, with varying effect on rate of aspiration events and other 
comorbidities (1, 3, 8). However, a fourth retrospective review of patients undergoing open 
esophagectomy, patients receiving botulinum injection experienced higher rates of gastric outlet 
obstruction, requiring additional procedures for pyloric dilation compared to patients undergoing 
pyloromyotomy or pyloroplasty (9). Although these studies were performed using the open 
esophagectomy technique, they highlight the issues with the data we currently base our practice 
on. These studies have all been underpowered or flawed, are retrospective in nature, and lack 
objective criteria in determining requirement for secondary intervention. We are unable to 
determine if botulinum toxin as a pyloric drainage procedure is a necessary step in an already 
complex operation. Standardized reporting of postoperative gastric outlet obstruction with delayed 
gastric emptying and thresholds for intervention are necessary to determine if botulinum toxin as 
a pyloric drainage procedure is a necessary step in an already complex operation. No prospective 
randomized study has been published, or to the author’s knowledge is in process, to assess the use 
of intra-pyloric botulinum toxin in the minimally invasive setting as a pyloric drainage procedure.
1.2
Risks and/or Benefits
Risks:
By omitting the pyloric botulinum toxin injection, there is a risk of delayed gastric emptying 
causing nausea, vomiting, aspiration, pneumonia, prolonged nasogastric decompression, inability 
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to tolerate oral diet and lengthening hospital stay. Delayed gastric emptying is a known 
complication after esophagectomy, and a common complication. This complication occurs even 
with botulinum injection in about 30% of patients (7). One published study concluded that patients 
receiving botulinum toxin injection experienced higher rates of delayed gastric emptying (9). In 
most cases of delayed gastric emptying, symptoms may be treated with medications and if severe, 
by endoscopic procedures, such as botulinum toxin injection or balloon dilation. Therefore, if a 
patient who did not receive pyloric botulinum toxin injection develops gastric outlet obstruction, 
he may undergo an endoscopic procedure to alleviate his symptoms. Rarely, severe delayed gastric 
emptying with complete obstruction may require a return to the operating room.
The drug used in this study is OnabotulinumtoxinA (botulinum toxin type A, Botox©). When 
injected intramuscularly, botulinum toxin inhibits the release of acetylcholine from nerve endings 
at neuromuscular junctions in the local muscle (10). Without release of acetylcholine, 
neurotransmission between peripheral nerve endings and muscle fibers cannot occur, and the 
muscle becomes weak or paralyzed (10). Botulinum toxin is used for cosmetic procedures, and is 
also FDA-approved to treat cervical dystonia, strabismus, and primary axillary hyperhidrosis (11). 
Off-label uses of botulinum toxin in the gastrointestinal tract include achalasia and refractory anal 
fissure, in addition to pyloric injection during esophagectomy. 
Benefits:
We hypothesize that pyloric botulinum toxin injection does not prevent delayed gastric emptying 
and is an unnecessary portion of the minimally invasive esophagectomy. If it is found that 
botulinum toxin injection does not lead to lower rates of delayed gastric emptying, then this 
procedure may be omitted, saving cost and side effects associated with the medication, and 
potential side effects of employing a pyloric drainage procedure, including pyloric edema, 
dumping syndrome and bile reflux. Pyloric edema from receiving botulinum toxin injection may 
actually cause delayed gastric emptying. The current rates of pyloric edema, dumping syndrome, 
and bile reflux are unclear at this time, and will be directly assessed in this study during the 
nuclear medicine emptying study.
2
RATIONALE
This study will help clarify if a pyloric drainage procedure is necessary in patients undergoing 
minimally invasive esophagectomy. Over the past ten years significant changes were made to 
esophagectomy technique including transition to minimally invasive technique, stapled technique 
for anastomosis and tissue transection and tubularization of the stomach conduit as opposed to use 
of whole stomach. With a narrower conduit, a drainage procedure may be unnecessary since the 
occurrence of redundancy and stasis is lower.
3
OBJECTIVES
3.1
Primary Objective

Determine if intra-pyloric botulinum toxin injection (Botox©) during a minimally invasive 
esophagectomy decreases postoperative occurrence of delayed gastric emptying. 
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3.2
Secondary Objectives

Determine if intra-pyloric botulinum toxin injection during a minimally invasive 
esophagectomy:
o
Reduces the number of repeat procedures for delayed gastric emptying within 90 
days, 
o
Decreases time to oral intake meeting 100% of nutritional requirements,
o
Reduces the incidence of pulmonary complications directly related to delayed 
gastric emptying,
o
Reduces hospital length of stay related to delayed gastric emptying and,
o
Increases patient quality of life
4
METHODOLOGY
4.1
Study Design
This is a double arm, single-blinded randomized trial evaluating the use of botulinum toxin 
injection as a pyloric drainage procedure. The study is expected to accrue patients over 4 years. 
The study schema is depicted below in Figure 1.
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Figure 1
Study Schema
All patients considered for minimally invasive esophagectomy in our surgery practice will receive 
routine work-up and multidisciplinary evaluation and care for esophageal carcinoma, which may 
include neoadjuvant therapy. Patients will be given a patient consent form that will inform them 
of the possible risks and benefits of this study. Patients will undergo the standard of care 
preoperative work-up, during which it will be determined if they meet the inclusion and exclusion 
criteria summarized in Section 5.1 and Section 5.2 prior to enrollment in the study. If criteria are 
met, patients will be randomized by the study coordinator, per methods determined by the 
statistician. The randomization allocation will be shared with the surgical team from the study 
coordinator to the surgeon prior to the surgery and discussed during the surgical time-out. The next 
50 patients who meet the study criteria will be randomized to either the intrapyloric botulinum 
injection arm or the non-botulinum treatment arm. All participants will sign a surgical consent 
prior to minimally invasive esophagectomy.
All patients will undergo routine minimally invasive esophagectomy. If randomized to the 
botulinum arm, patients will undergo the standard minimally invasive esophagectomy performed 
at RPCI, including intra-pyloric botulinum injection. If randomized to the no botulinum arm, 
patients will undergo the standard minimally invasive esophagectomy performed at RPCI 
excluding the pyloric drainage procedure with botulinum injection. The patient and radiologist 
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will be blinded to the treatment arm. The surgeon, due to the nature of the intervention, will not be 
blinded to the treatment arm.
The standard of care for minimally invasive esophagectomy at RPCI is outlined in the following 
postoperative pathway. All patients follow this pathway unless clinical status dictates 
otherwise: 

Patients leave the operating room with a nasogastric tube (NGT) tip at or beneath the 
esophago-gastric anastomosis, and a feeding jejunal-tube (j-tube).

Unless prohibited by medical condition, tube feeds are started through the j-tube at 
20 mL/hour. Tube feeds are advanced to goal after return of bowel function.

The NGT is removed.

If there is no concern for aspiration-such as hoarseness, altered mental status, or limited 
mobility, and the patient is alert and able to protect the airway, oral diet is started with sips 
of clear liquids.

Diet is advanced to full liquids. The nutritional goal, which continues at hospital discharge, 
is for the oral full liquid diet to meet 50% of calculated caloric needs, and the remaining 
50% given as supplemental tube feeds through the j-tube. Patients remain on a full liquid 
diet for two weeks postoperatively.

A gastrografin swallow study or CT esophagram is performed to evaluate for any signs of 
anastomotic leak. 
o
This study may also be used to assess gastric emptying. A single radiologist will 
evaluate the gastrografin study/CT esophagram (1): 
o
Quantifying gastric emptying by gastrografin swallow or CT esophagram will 
allow comparison of our results to previous nonrandomized studies (1).

Patients are discharged from the hospital if they are medically stable and tolerating 100% 
of nutritional needs as a combination of orally or through j-tube. Any clinical signs of 
delayed gastric emptying causing regurgitation, vomiting or aspiration will delay hospital 
discharge until the risk of aspiration is low.

The day that the first nutritional goal is met will be recorded, when 50% nutritional needs 
are met with oral full liquid intake and 50% supplemental tube feeds.

Hospital length of stay attributed to delayed gastric emptying: If patients have intractable 
nausea and vomiting, or experience a pulmonary event related to aspiration, this will be 
recorded as attributed to delayed gastric emptying. Prolonged hospital length of stay will 
be defined as hospital admission past Postoperative Day #14 attributed to delayed gastric 
emptying.

If it is uncertain whether a pulmonary event is related to delayed gastric emptying, a formal 
swallow evaluation will be performed by a speech language pathologist.
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
Patients will receive non-opiate and opiate pain relief medications in the postoperative 
period. Opiate pain medications should only be administered if adequate pain control is not 
met with non-opiate pain medications.
As a participant in this study the patient will undergo a nuclear medicine emptying study to assess 
for conduit function. This study will be obtained within the window of Postoperative Visit #2 (±14 
days). Prior to the nuclear medicine emptying study, the patient must be fasting for at least 6 hours; 
including oral intake and any supplemental j-tube feeds. The fasting glucose should be measured 
and less than 275 mg/dL. Patients should be off all narcotic pain medications for the 48 hours prior 
to the nuclear medicine emptying study.

120 mL of liquid egg white product (Egg Beaters) will be radiolabeled with 1 mCi of 
Tc99m, cooked and then scrambled. The patient will be instructed to ingest the meal within 
10 minutes. Images will be obtained every 15 minutes for up to four hours. If the patient 
vomits part of the meal at any time during the test, it will be recorded on the study report.

During the study, for the time between the images, the patients may be sitting, standing, or 
walking, but should remain in close proximity to the nuclear medicine facility. Patients will 
be monitored for any symptoms of delayed gastric emptying during this time. Participants 
will answer a questionnaire to assess for gastrointestinal symptoms during the nuclear 
medicine study (See Appendix C).
A single nuclear radiologist, who is blinded to the randomization group, will assess gastric 
emptying on the nuclear emptying study. There is no standardized method for reporting conduit 
emptying by this method. Two published studies on this topic have used time to 50% gastric 
emptying as an endpoint (8), and categorized 50% gastric emptying into ranges, with >180 minutes 
categorized as “delayed,” within 180 minutes as “intermediate,” and immediate emptying as 
“rapid” (12). We will measure time to 50% gastric emptying in all patients, and categorize similar 
to the above description, as follows:
Table 1
50% Gastric Emptying Times and Definitions:
Definition
50% Emptying Time
Rapid
Immediate emptying, no radiotracer seen on 
first image obtained at 15 minutes
Intermediate
< or = 150 minutes
Delayed
> 150 minutes
This time modification is based on the current guidelines and normal limits for gastric retention 
assessed by nuclear scanning (13). The report will also include the percentage of tracer retained 
the following times after meal ingestion: 1, 2, 3, and 4 hours.
To ensure the radiologist interpreting the nuclear medicine and gastrografin studies/CT 
esophagram remains blinded, the radiologist should not open the “operative note” documents in 
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the electronic medical record. During study interpretation, if the radiologist requires clarification 
regarding the operative procedure, he should contact the operating surgeons directly. The 
randomization group will not be listed in any other part of the electronic medical record.
Primary Endpoint

Postoperative delayed gastric emptying assessed radiographically as “severe” by nuclear 
medicine emptying study compared to “intermediate,” and “rapid” emptying. “Severe” 
delayed gastric emptying will be defined as scoring of “delayed” on nuclear emptying 
study. Patients assessed as “intermediate” or “rapid” on nuclear medicine emptying study 
will be considered to have normal conduit function.
Secondary Endpoints

Postoperative delayed gastric emptying assessed radiographically by gastrografin swallow 
/CT esophagram. 

Postoperative delayed gastric emptying assessed clinically by the following:
1. Quality of life score assessed by EORTC QLQ-C30 OES18.
2. Pulmonary events directly related to delayed gastric emptying, as assessed by the 
operating surgeon. Pulmonary events include pneumonia, acute aspiration, and 
respiratory failure requiring intubation.
3. Gastrointestinal and nutritional status: Requirement of NGT past Postoperative 
Day #7, or need to reinsert NGT, witnessed nausea, vomiting, or regurgitation 
directly related to delayed gastric emptying. This does not include postoperative ileus. 
Tolerance of full liquid diet at hospital discharge and meeting nutritional goals of 
time to resumption of 50% caloric needs orally by Postoperative Day #7, 75% caloric 
needs orally by Postoperative Day #21, and 100% caloric needs orally by 
Postoperative Day #35.
o
“Moderate” delayed gastric emptying will be defined as clinical symptoms 
requiring medical therapy.
o
“Severe” delayed gastric emptying will be defined as clinical symptoms requiring 
secondary procedure.
4. Hospital length of stay attributed to delayed gastric emptying.
5. Number of secondary procedures within 90 days due to delayed gastric emptying. 
Secondary procedures include endoscopic or operative procedures for delayed gastric 
emptying.
o
Requirement of secondary procedure will be graded as “Severe” delayed gastric 
emptying
4.2
Target Accrual and Study Duration
A maximum of 50 evaluable patients at RPCI will be enrolled. Accrual is expected to take up to 
6 years.
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This target accrual and study duration is highly feasible based off the high volume of patients with 
esophageal carcinoma undergoing minimally invasive esophagectomy at RPCI. An interim 
analysis will occur after 30 patients have been enrolled.
Study participants will be followed for data collection for 90 days (routine post-esophagectomy 
follow-up care and surveillance, per standard of care).
A patient will be replaced on study if the following deviations from the original surgical plan 
occur:

the surgical procedure is converted to open technique or,

a cervical anastomosis is performed or,

a patient does not complete the postoperative evaluation through the nuclear medicine 
emptying study obtained within ± 14 days of post-operative visit #2.
5
PARTICIPANT SELECTION
5.1
Inclusion Criteria
To be included in this study, participants must meet the following criteria:
1. Esophageal carcinoma, undergoing minimally invasive esophagectomy with intrathoracic 
anastomosis. 
2. Age ≥ 18 years of age.
3. Have an ECOG Performance Status of ≤ 2. Refer to Appendix A.
4. Participant must understand the investigational nature of this study and sign an Independent 
Ethics Committee/Institutional Review Board approved written informed consent form 
prior to receiving any study related procedure.
5.2
Exclusion Criteria
Participants will be excluded from this study for the following:
1. Patients who have a history of gastrointestinal dysmotility or functional gastroparesis, 
including diabetic gastroparesis, central and peripheral nervous system disorders, renal 
failure, medication side effects, including chronic dependence of promotility agents, 
anticholinergic antispasmodic agents, or chronic narcotic use over 2 years due to non-
cancer causes. Refer to Appendix B for a list of pharmacologic agents.
2. Patients who have a history of previous gastric or duodenal surgery.
3. Patients who have a history of duodenal ulcer or duodenal fibrosis.
4. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study requirements.
5. Allergy to botulinum toxin, and or egg.
6. Pregnant or nursing female participants.
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7. Unwilling or unable to follow protocol requirements.
8. Any condition which in the Investigator’s opinion deems the participant an unsuitable 
candidate for study participation.
5.3
Inclusion of Women and Minorities
Both men and women and members of all races and ethnic groups are eligible for this study.
6
STUDY PROCEDURES
The study-specific assessments are detailed in this section and outlined in Table 2 (Schedule of 
Procedures and Observations). Standard preoperative screening assessment and multidisciplinary 
evaluation must be performed up to 6 weeks prior to minimally invasive esophagectomy. The 
nuclear medicine emptying study may occur within the window of Postoperative Visit #2 (± 
14 days) unless contraindicated per physician’s discretion. Unless otherwise defined in the written 
protocol text, all procedures/assessments will be conducted in accordance with RPCI Clinical 
Research Services Standard Operating Procedures. All procedures and evaluations listed are our 
post-esophagectomy standard of care at RPCI except for Nuclear Medicine Emptying Study, 
EORTC QLQ OES18 Questionnaire, and routine postoperative outpatient assessment by our 
dietician.
6.1
Participant Randomization and Registration
Eligibility of each participant will be established prior to randomization.
Informed consent MUST be completed prior to receiving any study related procedures.
Participants will be randomized in a 1:1 fashion to the botulinum and non-botulinum treatment 
arms using a permuted block design. The randomization list will be developed by the Department 
of Biostatistics and Bioinformatics, and randomization procedure as outlined in Section 9.2.
6.2
Baseline Evaluations
Preoperative workup and multimodality therapy for esophageal cancer as standard of care at RPCI, 
based upon the NCCN guidelines for esophageal cancer. Standard presurgical assessment with full 
medical history and physical examination, laboratory tests, cross-sectional imaging and 
cardiopulmonary assessment as determined by the operating surgeon or the Preoperative 
Anesthesia Clinic based upon RPCI established guidelines. 
The following will be performed prior to the participant’s scheduled minimally invasive 
esophagectomy and will be confirmed before surgery:

Informed consent for study. Must be completed prior to receiving any study-related 
procedures.

Medical history with preexisting conditions, including all neoadjuvant therapy related to 
esophageal carcinoma, smoking status and, diabetes.
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
Physical examination, including vital signs (i.e., temperature, heart rate, respiratory rate, 
blood pressure), body weight and height; with emphasis on the neck, thoracic, and 
abdominal cavities.

Multidisciplinary evaluation and neoadjuvant therapy if indicated for esophageal 
carcinoma. Multidisciplinary evaluation will be documented in the outpatient preoperative 
office visit note.

Pregnancy test (urine) in females of childbearing potential. The standard operating 
procedure for all females of childbearing potential in the Ambulatory Surgical Center 
(ASC) pre-op holding area is to obtain a urine HCG. This study protocol does not deviate 
from the standard operating procedure of the ASC/pre-op holding area at RPCI. If the 
pregnancy test is positive, the patient is excluded from the study.

Nutritional status assessment by a dietician, as clinically indicated.
The following will be performed if indicated by the anesthesia pre-op assessment (standard 
operating procedure for the pre-op clinic at RPCI). These tests are not strictly required to support 
eligibility for this study, but if indicated and performed, may exclude the patient from receiving a 
general anesthetic and thereby excluding the patient from this study.

Hematology: CBC with automated differentials (WBC, RBC, HGB, HCT, platelet, MCV, 
MCH, MCHC, % neutrophils, absolute neutrophils, % monocytes, absolute monocytes, % 
eosinophils, absolute eosinophils, % basophils, absolute basophils, % lymphocyte, absolute 
lymphocyte, platelet confirmation (as clinically indicated), and differential confirmation 
(as clinically indicated).

Chemistry (i.e., complete metabolic panel (CMP): chloride, CO2, potassium, sodium, 
BUN, glucose, calcium, creatinine, total protein, albumin, total bilirubin, alkaline 
phosphatase, AST, ALT, A/G ratio, BUN/creatinine ratio, osmol (Calc), anion gap).

12-lead electrocardiogram, chest x-ray, pulmonary function tests, and cardiac stress test, if 
indicated.
6.3
Treatment

If criteria are met, patients will be randomized by the study coordinator, per methods 
determined by the statistician. The randomization allocation will be shared with the 
surgical team from the study coordinator to the surgeon prior to the surgery.
o
If randomized to the botulinum arm, patients will undergo the standard minimally 
invasive esophagectomy performed at RPCI, including botulinum injection. The 
intraoperative procedure for botulinum toxin injection is as follows: 100 units of 
botulinum toxin is dissolved in 10 mL normal saline. After preparation of the 
gastric conduit, including mobilization and transection, the 10 mL of botulinum 
toxin solution is injected with a thoracoscopic needle intramuscularly at the anterior 
pyloric ring, in 2-3 separate areas.
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o
If randomized to the no botulinum arm, patients will undergo the standard 
minimally invasive esophagectomy performed at RPCI excluding the pyloric 
drainage procedure with botulinum injection.

Standard Post Anesthesia Care Unit (PACU) protocols for patient recovery from surgery. 
Patients will be continuously monitored both intraoperatively and during the recovery 
period. 

 Clinical Events of Interest and Adverse Events will be recorded throughout the time of 
entry into the operating room until the post-operative follow-up. Refer to Section 7.1.3 for 
method of recording clinical events of interest and adverse events.
6.4
Inpatient Postoperative Follow-Up Evaluations
The following evaluations will be performed during the inpatient postoperative course (surgery 
to discharge), unless otherwise clinically indicated.:
Patients will follow Roswell Park standard of care postoperative pathway for minimally invasive 
esophagectomy (refer to Section 4.1), unless otherwise clinically indicated. This includes:

Initial postoperative care in the intensive care unit or intermediate care unit, based on 
clinical status, with nursing care and vital signs per hospital unit standard:

At the minimum daily physical examination (including vital signs).

Laboratory analysis, including hematology (CBC with automated differentials) and 
chemistry (CMP), at least on a daily basis until Postoperative Day 6.

Standard inpatient postoperative evaluations after minimally invasive esophagectomy 
include daily chest x-ray for at least four days postoperatively, and occasionally a CT scan 
of the chest if clinically indicated.

Gastrografin swallow study/CT esophagram is obtained to evaluate for any signs of 
anastomotic leak. 

Clinical evaluation of symptoms will be evaluated by the participant’s care team, including 
inpatient nurses, mid-level providers, surgical fellows, operating surgeon, speech therapist, 
occupational or physical therapists, dieticians, and documented in the RPCI electronic 
medical record (EMR).

Speech therapy evaluation for any dysphagia or signs of aspiration.

Nutritional assessments will be performed by a dietician familiar with the study. The initial 
evaluation will be performed in the outpatient setting if there are signs of malnutrition or 
inability to tolerate oral intake at the preoperative visit. Otherwise the standard is to 
perform the initial nutritional assessment in the immediate postoperative period. Patients 
will be monitored by the dietician Monday-Friday while an inpatient, and then at each 
subsequent follow-up office visit, and assessment documented in the RPCI EMR. 

Nutritional goals are as follows: By hospital discharge, patients are expected to meet 50% of 
their total nutritional requirements orally and 50% by supplemental j-tube feeds. On 
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Postoperative Day #6, ± 1 day, patients will undergo a 24-hour calorie count, to objectively 
assess oral intake. By Postoperative Day #21, patients should meet 75% nutritional 
requirements orally and 25% j-tube feeds, and by postoperative week #5, 100% oral calories. 
The postoperative day that each of these goals are met will be recorded (Day tolerating 50% 
oral feeds, 75% oral feeds, 100% oral feeds).

Concomitant medication: List any ongoing medications with dose changes, as applicable. 
Patients may take opiates in the postoperative period, including on the day of the 
gastrografin swallow study/CT esophagram, and type and dosage will be recorded.

Clinical Events of Interest and Adverse Events
Patients will be discharged from the hospital if they are medically stable and tolerating 100% of 
nutritional needs with a combination of orally and supplemental through j-tube:

Any clinical signs of delayed gastric emptying causing regurgitation, vomiting, or 
aspiration will delay hospital discharge until the risk of aspiration is low.

Hospital length of stay attributed to delayed gastric emptying: If patients have intractable 
nausea and vomiting, or experience a pulmonary event related to aspiration, this will be 
recorded as attributed to delayed gastric emptying.
6.5
Criteria for Retreatment

Patients with “severe” delayed gastric emptying assessed radiographically or clinically at 
any time will be considered for endoscopic procedures for gastric outlet obstruction, 
including pyloric botulinum toxin injection or balloon dilation, or operative procedure. 
This is irrespective of whether a patient was initially treated with botulinum toxin at the 
minimally invasive esophagectomy; patients randomized to the botulinum toxin group may 
undergo additional botulinum toxin injection endoscopically. The maximum dose of 
botulinum toxin a patient may receive for this study in the three-month period is 300 units. 
Each of these procedures- when a patient undergoes a therapeutic endoscopic procedure or 
returns to the operating room- will be defined as a secondary procedure.

 Development of “severe” delayed gastric emptying as assessed by nuclear medicine study 
will be considered a failure of the experimental procedure and will be included in the 
primary analysis. Requirement for secondary procedure or development of “severe” 
delayed gastric emptying as assessed by parameters other than the nuclear medicine study 
will be included in the secondary analysis. 

Patients with “moderate” delayed gastric emptying assessed radiographically or clinically 
at any time will be considered for initiation of promotility agents. Development of 
“moderate” delayed gastric emptying will be included in the secondary analysis.
6.6
Outpatient Postoperative Follow-Up Visits
Study participants will be followed for data collection for 90 days (routine post-esophagectomy 
follow-up and surveillance, per standard of care). The following evaluations will be performed 
during the outpatient postoperative course, unless otherwise clinically indicated:
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
In the postoperative period, patients return to office for outpatient follow-up approximately 
one to three weeks after discharge (“Postoperative Visit #1”). This visit is standard of care 
and can be scheduled per PI discretion. Physical exam and vital signs will be conducted at 
this visit. The dietician will assess oral intake, and supplemental tube feeds adjusted 
accordingly. Day until patient tolerates 75% and 100% of nutritional needs orally will be 
recorded as per nutritionist assessment. 

As a participant in this study, patients in both randomization groups will undergo a nuclear 
medicine emptying study The nuclear medicine emptying study may occur within the 
window of Postoperative Visit #2 (± 14 days ) to assess dynamic conduit function. This 
test can be extended beyond post-operative Visit #2 at PI’s discretion. Patients will be 
monitored for any symptoms of delayed gastric emptying during this time by questionnaire 
(See Appendix C), to determine if nuclear medicine study findings correlate with 
concurrent clinical symptoms.
o
Prior to the nuclear medicine emptying study, the patient must be fasting for at 
least 6 hours, including oral intake and any supplemental j-tube feeds. If the 
patient is a diabetic, the glucose level should be measured and less than 275 
mg/dL within 2 hours of the study. Opiates must be held for 48 hours prior to the 
study. Patients should not be on any of the medications listed in Appendix B 
within the 48 hours prior to the study. Patients will remain in the nuclear medicine 
suite during this time, and will be required to sit upright, and may walk around the 
room. During the study, for the time between the images, the patients may be 
sitting, standing, or walking, but should remain in close proximity to the nuclear 
medicine facility.

Post-surgical symptom evaluation based on clinical factors during the outpatient follow-up 
visits, and additionally by phone conversation between outpatient follow-up appointments 
if clinically indicated.

At Postoperative Visit #2, patients will be assessed for quality of life as measured by 
EORQLQ-C30 OES18 questionnaire (Appendix D). This will usually occur in the office 
around postoperative week six to eight. However, if the patient remains hospitalized during 
this time point, the questionnaire will be administered once between Postoperative Days 
35-42. 

Concomitant medications: List any ongoing medications with dose changes, as applicable.

Clinical Events of Interest and Adverse Events
Participants who are unavailable for follow-up evaluations should be classified as lost to follow-
up for one of the following reasons:

Lost to follow-up: For a participant to be considered lost to follow-up, the investigator must 
make two separate attempts to re-establish contact with the participant. The attempts to re-
establish participant contact must be documented (e.g., certified letter).
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
Death: Date and cause of death will be recorded for those participants who die within 
30 days of surgery (telephone verification is acceptable).
6.7
End of Study Visit

At day #90 (± 7 days), an end of study phone call will be conducted by the study 
coordinator. The purpose of this call is to inquire about any subsequent procedures the 
patient may have undergone related to delayed gastric emptying or esophagectomy, 
nutrition assessment to determine if the patient continues to require supplemental jejunal 
feeds, any persistent clinical symptoms of delayed gastric emptying, including any 
subsequent pneumonia, aspiration events, respiratory failure, nausea, vomiting, ability to 
eat solid food or drink liquids or having any trouble eating, early satiety, difficulty 
swallowing saliva, noticing bile or green staining on pillow while sleeping, experiencing 
acid indigestion or heartburn, or pain with eating,  concomitant medications and Clinical 
Events of Interest and adverse events will be assessed. If the patient indicates continued 
use of tube feeds, the study coordinator will alert the dietician to call the patient for further 
evaluation of the percentage of tube feeds versus oral intake. If the patient is no longer 
using jejunal feeds, the study coordinator will mark down “100% oral intake.
The schedule of procedures and observations for this study is summarized in Table 2 below.
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Table 2
Schedule of Procedures and Observations
Evaluation
Baseline1
Day of 
Surgery
Inpatient 
Postoperative 
Course2 
(Surgery to 
Discharge)
Postoperative Visit #13 
± 14 days
Postoperative 
Visit#23 ± 14 days
End of Study phone call
Day#90
(± 14 days)
Medical History, Pre-
Existing Conditions 
(including smoking 
status, diabetes)
X
ECOG Performance 
Status
X
Multidisciplinary 
Evaluation and 
neoadjuvant therapy 
for esophageal 
carcinoma
X
Physical Examination, 
including vital signs4
X
X
X
X
X
Hematology5
X
X
X
Chemistry6
X
X
X
Sign study informed 
consent, if eligible 
based on above 
factors
X
Minimally invasive 
esophagectomy with 
or without pyloric 
drainage procedure
X
Fasting glucose
X As indicated)
Chest X-Ray, CT 
chest
X (As indicated)
X (As indicated)

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Evaluation
Baseline1
Day of 
Surgery
Inpatient 
Postoperative 
Course2 
(Surgery to 
Discharge)
Postoperative Visit #13 
± 14 days
Postoperative 
Visit#23 ± 14 days
End of Study phone call
Day#90
(± 14 days)
Gastrografin swallow 
evaluation12 /CT 
esophagram
X12a
Nuclear Medicine 
Emptying Study10, 11
X11 (Phone call prior to give 
instructions)
Clinical Evaluation of 
Symptoms
X
X11
X
X
Medical evaluation 
(signs of pneumonia, 
aspiration)
X
X
X
Nutrition evaluation13
X (As 
indicated)
X14
X
X
X (As indicated)
EORTC QLQ OES18 
Questionnaire10 See 
Appendix D
X
Pregnancy 
Test7(Urine)
X
Electrocardiogram, 
Chest x-ray, and/or 
Pulmonary Function 
tests
X (As 
indicated)
Speech therapy 
evaluation
X (As indicated)
Concomitant 
Medications
X8
X
X
X
X
X
Clinical Events of 
Interest and AEs
X9
X
X
X
X

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Evaluation
Baseline1
Day of 
Surgery
Inpatient 
Postoperative 
Course2 
(Surgery to 
Discharge)
Postoperative Visit #13 
± 14 days
Postoperative 
Visit#23 ± 14 days
End of Study phone call
Day#90
(± 14 days)
Fasting glucose (for 
patients with diabetes)
 
 
  
 
X (As indicated)
 
1
Baseline evaluations will be performed prior to the participant’s scheduled minimally invasive esophagectomy and will be confirmed before surgery 
(Preoperative workup and multimodality therapy for esophageal cancer as standard of care at Roswell Park and based upon the NCCN guidelines for 
esophageal cancer. Refer to Section 6.2).
2
Patients will follow the standard of care postoperative pathway for minimally invasive esophagectomy.
3
Initial Standard of Care postoperative follow-up visit (Postoperative Visit #1) after hospital discharge, and then again at Postoperative Visit #2 if the 
postoperative course is uncomplicated.  If complications arise, patients may be seen more often in follow-up. Patients will be followed for data collection 
for 90 days following surgery. 
4
Vital signs (temperature, heart rate, respiratory rate, blood pressure), body weight and, height. Height collected at baseline only.
5
If indicated by the anesthesia pre-op assessment- Hematology: CBC with automated differentials (WBC, RBC, HGB, HCT, platelet, MCV, MCH, 
MCHC, % neutrophils, absolute neutrophils, , % monocytes, absolute monocytes, % eosinophils, absolute eosinophils, % basophils, absolute basophils, % 
lymphocyte, absolute lymphocyte, platelet confirmation (as clinically indicated), and differential confirmation (as clinically indicated). 
6
If indicated by the anesthesia pre-op assessment - Chemistry: CMP (chloride, CO2, potassium, sodium, BUN, glucose, calcium, creatinine, total protein, 
albumin, total bilirubin, alkaline phosphatase, AST, ALT, A/G ratio, BUN/creatinine ratio, osmol (Calc), anion gap), as clinically indicated.
7
To be performed < 1 week prior to scheduled surgery,
8
Medications ongoing, or discontinued, within 1 week prior surgery.
9
To be recorded from the time of entry into the operating room until the post-operative follow up. Clinical Events of Interest and SAEs will be recorded in 
the electronic medical record, and found in the patient’s operative note, anesthesia records, daily progress notes, consult notes, nutrition notes, and 
outpatient visit notes.
10
All procedures and evaluations listed are our post-esophagectomy standard of care at RPCI except for Nuclear Medicine Emptying Study, EORTC QLQ 
OES18 Questionnaire, and routine postoperative assessment by dietician. See Table 1 for definitions, section 4.1. If contraindicated per investigator’s 
discretion, the nuclear medicine emptying study can be extended beyond post-operative Visit #2 at PI’s discretion. 
11
Evaluation as documented in Appendix C, Nuclear Medicine Questionnaire.
12
 CT esophagram or gastrografin swallow.
12a: As inpatient when clinically indicated.
13
Nutritional goals as defined in Section 6.4: Day tolerating 50% oral feeds, 75% oral feeds, 100% oral feeds.
14
Nutrition assessment will include a 24-hour calorie count on Postoperative Day #6 ±1 day.
 

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6.8
Compliance
The patient must attend his/her post-operative appointments in the ninety days after surgery to 
evaluate for any signs of delayed gastric emptying.
7
SAFETY EVALUATION
7.1
Clinical Events of Interest and Adverse Events
Clinical events of interest (captured in REDCap) include, but are not limited to: patient continues 
to require supplemental jejunal feeds, persistent clinical symptoms of delayed gastric emptying 
(delayed gastric emptying assessed by the gastrografin swallow exam/CT esophagram), 
subsequent pneumonia, aspiration events, respiratory failure requiring reintubation, nausea, 
vomiting, ability to eat solid food or drink liquids or having any trouble eating, early satiety, 
difficulty swallowing saliva, bile or green staining on pillow while sleeping, experiencing acid 
indigestion or heartburn, pain with eating, additional postop procedures, EORTC QLQ-30 QoL 
scores, and hospital length of stay.
7.1.1
Definition of Adverse Events
An adverse event or adverse experience (AE) is any untoward medical occurrence associated with 
the use of a drug in humans, whether or not considered drug related. Therefore, an AE can be ANY 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or not 
considered related to the medicinal (investigational) product (attribution of ‘unrelated’, ‘unlikely’, 
‘possible’, ‘probable’, or ‘definite’).
An AE is considered “unexpected” if it is not listed in the investigator brochure or is not listed at 
the specificity or severity that has been observed; or if an investigator brochure is not required or 
available, is not consistent with the risk information described in the general investigational plan 
in other study-related documents.
7.1.1.1 Diagnosis Versus Signs and Symptoms
If known, a diagnosis should be recorded on the CRF rather than individual signs and symptoms 
(e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and elevated 
transaminases). However, if a constellation of signs and/or symptoms cannot be clinically 
characterized as a single diagnosis or syndrome at the time of reporting, each individual event 
should be recorded as an AE or SAE on the CRF. If a diagnosis is subsequently established, it 
should be reported as follow-up information.
7.1.1.2 Adverse Events Occurring Secondary to Other Events
In general, AEs occurring secondary to other events (e.g., cascade events or clinical sequelae) 
should be identified by their primary cause. For example, if severe diarrhea is known to have 
resulted in dehydration, it is sufficient to record only diarrhea as an AE or SAE on the CRF.
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However, clinically significant AEs occurring secondary to an initiating event that are separated 
in time should be recorded as independent events on the CRF. For example, if a severe 
gastrointestinal hemorrhage leads to renal failure, both events should be recorded separately on 
the CRF. Pain will not be considered an adverse event at any point, given the nature of the 
intervention (surgical procedure).
7.1.1.3 Abnormal Laboratory Values
Only clinically significant laboratory abnormalities that require active management will be 
recorded as AEs or SAEs on the CRF (e.g., abnormalities that require study drug dose 
modification, discontinuation of study treatment, more frequent follow-up assessments, further 
diagnostic investigation, etc.).
If the clinically significant laboratory abnormality is a sign of a disease or syndrome (e.g., alkaline 
phosphatase and bilirubin 5 x the upper limit of normal associated with cholecystitis), only the 
diagnosis (e.g., cholecystitis) needs to be recorded on the Adverse Event CRF.
If the clinically significant laboratory abnormality is not a sign of a disease or syndrome, the 
abnormality itself should be recorded as an AE or SAE on the CRF. If the laboratory abnormality 
can be characterized by a precise clinical term, the clinical term should be recorded as the AE or 
SAE. For example, an elevated blood  potassium level of 7 mEq/L should be recorded as 
“hyperkalemia.”
Observations of the same clinically significant laboratory abnormality from visit to visit should 
not be repeatedly recorded as AEs or SAEs on the CRF, unless their severity, seriousness, or 
etiology changes.
7.1.1.4 Preexisting Medical Conditions (Baseline Conditions)
A preexisting medical condition should be recorded as an AE or SAE only if the frequency, 
severity, or character of the condition worsens during the study. When recording such events on 
an Adverse Event CRF, it is important to convey the concept that the preexisting condition has 
changed by including applicable descriptors (e.g., “more frequent headaches”).
7.1.2
Drug Information- Botulinum toxin
OnabotulinumtoxinA (botulinum toxin type A, Botox©) inhibits the release of acetylcholine from 
nerve endings at neuromuscular junctions in the local muscle (10). Without the release of 
acetylcholine, neurotransmission between peripheral nerve endings and muscle fibers cannot 
occur, and the muscle becomes weak or paralyzed (10). The inhibitory effect of botulinum toxin 
is temporary, and muscle function recovers at 3 months after administration. The effect is not 
immediate, and rather occurs within 1-3 days.
With intramuscular injection at a dose of 100 units, botulinum toxin is not expected to be in contact 
with the peripheral blood (10). In rare instances, botulinum toxin may spread from the area of 
injection and produce symptoms consistent with botulinum toxin effects (13). These unanticipated 
symptoms may include asthenia, diplopia, ptosis, dysphagia, dysphonia, urinary incontinence, and 
breathing difficulties. These symptoms have been reported hours to weeks after injection. 
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Incidence of side-effects depends on injection site location. For example, patients treated with 
botulinum toxin injection into the sternocleidomastoid muscle for cervical dystonia are more likely 
to have the side-effects of swallowing difficulties, due to local diffusion. Swallowing and breathing 
difficulties may be life-threatening, and there have been reports of death (11). Patients with history 
of underlying conditions predisposing to muscle weakness have an increased risk of these side 
effects occurring (11). However, due to the nature of this study, patients with underlying muscle 
weakness are excluded from this study.
The maximum recommended dose of OnabotulinumtoxinA, regardless of the indication, is 
400 units over three months (10). Cervical dystonia is treated with doses ranging from 198-
300 units, divided among the affected muscle, with maximum dose 50 units per site. Our proposed 
dosage, 100 units in divided doses into the pyloric muscle, is within the range used among other 
high-volume esophagectomy centers (2, 3, 8, 9).
Absolute contraindications to botulinum toxin injection include previous hypersensitivity to the 
product (10). Mild to moderate side effects are generally mild transient, and include swelling or 
bruising at the injection site, and the small possibility of infection at injection site (10). 
Anaphylaxis/hypersensitivity reactions have occurred (11). Higher doses or more frequent 
administration may result in neutralizing antibody formation and loss of efficacy (10). This 
summary 
of 
the 
US 
FDA 
boxed 
warning 
may 
also 
be 
found 
at: 
http://www.fda.gov/downloads/Drugs/DrugSafety/UCM176360.pdf 
7.1.3
Grading and Relationship to Study Procedure
The descriptions and grading scales found in the CTEP Version 4 of the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) will be utilized for AE reporting. CTEP
Version 4 of the CTCAE is identified and located at:
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.
AEs not covered by specific terminology listed should be reported with common medical 
terminology and documented according to the grading scales provided in the CTCAE Version 4.
The relationship of event to study procedure will be documented by the Investigator as follows:

Unrelated: The event is clearly related to other factors such as the participant’s clinical state, 
other therapeutic interventions or concomitant drugs administered to the participant.

Unlikely: The event is doubtfully related to investigational agent(s). The event was most likely 
related to other factors such as the participant’s clinical state, other therapeutic interventions, 
or concomitant drugs.

Possible: The event follows a reasonable temporal sequence from the time of drug 
administration but could have been produced by other factors such as the participant’s clinical 
state, other therapeutic interventions or concomitant drugs.

Probable: The event follows a reasonable temporal sequence from the time of drug 
administration and follows a known response pattern to the study drug. The event cannot be 
reasonably explained by other factors such as the participant’s clinical state, therapeutic 
interventions or concomitant drugs.
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
Definite: The event follows a reasonable temporal sequence from the time of drug 
administration, follows a known response pattern to the study drug, cannot be reasonably 
explained by other factors such as the participant’s condition, therapeutic interventions or 
concomitant drugs; AND occurs immediately following study drug administration, improves 
upon stopping the drug, or reappears on re-exposure.
7.1.4
Reporting Adverse Events
Table 43
Guidelines for Routine Adverse Event Reporting for Phase 2 Studies 
(Regardless of Expectedness)
Attribution
Grade 1
Grade 2
Grade 3
Grade 4
Unrelated
X
X
Unlikely
X
X
Possible
X
X
X
X
Probable
X
X
X
X
Definite
X
X
X
X
Routine AEs occurring between the starting date of intervention until 30 days after the last 
intervention, or until the event has resolved, the study participant is lost to follow-up, the start of 
a new treatment, or until the study investigator assesses the event(s) as stable or irreversible, will 
be reported. New information will be reported after it is received.
7.2
Serious Adverse Events
7.2.1
Definition
A serious adverse event (SAE) is any adverse event (experience) that in the opinion of either the 
investigator or sponsor results in ANY of the following:

Death.

A life-threatening adverse event (experience). Any AE that places a participant or participants, 
in the view of the Investigator or sponsor, at immediate risk of death from the reaction as it 
occurred. It does NOT include an AE that, had it occurred in a more severe form, might have 
caused death.

Inpatient hospitalization or prolongation of existing hospitalization (for > 24 hours).

A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions.

A congenital anomaly or birth defect.

Important Medical Event (IME) that, based upon medical judgment, may jeopardize the 
participant and may require medical or surgical intervention to prevent one of the outcomes 
listed above.
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7.2.2
Reporting Serious Adverse Events
All new SAEs occurring from the date the participant signs the study consent until 90 days after 
the last intervention or a new treatment is started, whichever comes first, will be reported. The 
RPCI SAE Source Form is to be completed with all available information, including a brief 
narrative describing the SAE and any other relevant information. 
SAEs occurring after the 90 day follow-up period that the investigator determines to be possibly, 
probably or definitely related to the study intervention should be reported.
SAEs that are unexpected and possibly, probably or definitely related must be reported as an 
Unanticipated Problem. Please refer to Section 7.4 for details on reporting Unanticipated 
Problems.
7.3
Follow-Up for Serious Adverse Events
All related SAEs should be followed to their resolution, until the study participant is lost to 
follow-up, the start of a new treatment, or until the study investigator assesses the event(s) as stable 
or irreversible. New information will be reported when it is received.
7.4
Unanticipated Problems
7.4.1
Definition
An Unanticipated Problem (UP) is any incident, experience, or outcome that meets all of the 
following criteria:

Unexpected (in terms of nature, severity, or frequency) given:
a) The research procedures that are described in the study-related documents, including 
study deviations, as well as issues related to compromise of participant privacy or 
confidentiality of data.
b) The characteristics of the participant population being studied.

Related or possibly related to participation in the research (possibly related means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research).

Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized 
or if in relation to an AE is deemed Serious per Section 7.2.
7.4.2
Reporting Unanticipated Problems
The Reportable New Information (RNI) Form will be submitted to the CRS Quality Assurance 
(QA) Office within 1 business day of becoming aware of the Unanticipated Problem. After review, 
the CRS QA Office will submit the RNI to the IRB.
When becoming aware of new information about an Unanticipated Problem, submit the updated 
information to the QA Office with an updated Reportable New Information Form. The site 
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Investigator or designated research personnel will report all unanticipated problems to the IRB in 
accordance with their local institutional guidelines.
8
DATA AND SAFETY MONITORING
The Roswell Park Data Safety Monitoring Committee will assess the progress of the study, the 
safety data, and critical efficacy endpoints (Phase I studies will be reviewed quarterly; Phase II, 
III and pilot investigator-initiated studies will be reviewed semi-annually). The DSMC will review 
the study and will make recommendations that include but not limited to; (a) continuation of the 
study, (b) modifications to the design (c) suspension of or (d) termination of the study
9
STATISTICAL METHODOLOGY
The primary objectives of this study are:

Determine if intra-pyloric botulinum toxin injection during a minimally invasive 
esophagectomy decreases postoperative occurrence of delayed gastric emptying, as assessed 
radiographically by nuclear medicine emptying study.
The secondary objectives of this study are:

Determine if intra-pyloric botulinum toxin injection during a minimally invasive 
esophagectomy reduces the number of repeat procedures for delayed gastric emptying within 
90 days, decreases time to oral intake meeting 100% of nutritional requirements, reduces the 
incidence of pulmonary and gastrointestinal complications directly related to delayed gastric 
emptying, reduces hospital length of stay related to delayed gastric emptying, and increases 
patient quality of life.
9.1
Sample Size Determination
The sample size justification is based on the primary analysis. We consider a study design with a 
total sample of n=50 patients (randomly assigned in a 1:1 fashion to the Botox and non-Botox 
treatment arms) and an interim analysis at n1=30. The performance of this study design and 
decision rules (described in the primary analysis) was assessed via simulation study.
If the true rates of delayed gastric emptying are 0.30 and 0.70 in the Botox and non-Botox 
treatment arms, then the study design achieves 85.0% power to detect a significant change in the 
delayed gastric emptying rates at a significance level of 0.05. The chance of stopping early for 
superiority is 42.8%, while the chance of stopping early due to inferiority is only 1.0%.
If the true rate of delayed gastric emptying is 0.70 in both treatment arms, then there is a 4.3% 
chance of falsely identifying the Botox arm as superior (observed type I error rate), a 0.9% chance 
of stopping early for superiority, and a 42.1% chance of stopping early for inferiority.
9.2
Randomization
Patients will be randomized in a 1:1 fashion to the Botox and non-Botox treatment arms using a 
permuted block design. Participants will be stratified on the receipt of neoadjuvant 
chemoradiotherapy, smoking status, and diabetes. Participants will be randomized prior to the 
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minimally invasive esophagectomy, after signing consent for the surgical procedure. The 
randomization list will be developed by the Department of Biostatistics and Bioinformatics and 
provided to the study coordinator, who will then relay the information to the surgical team at the 
start of the procedure.
9.3
Demographics and Baseline Characteristics
Descriptive statistics (as appropriate: n, percent, mean, median, min and max) will be used to 
summarize demographic and baseline characteristics.
9.4
Primary and Secondary Analyses
Primary Analysis: A recent study demonstrated that patients who received Botox had a delayed 
gastric emptying rate of approximately 30% as compared to a complication rate in historical 
controls of 70% in patients that did not receive botulinum toxin injection (7). A retrospective 
review of patients undergoing minimally invasive esophagectomy at Roswell Park Cancer Institute 
indicates that the rate of postoperative delayed gastric emptying is even lower, however, this rate 
is based on very stringent criteria for delayed gastric emptying- requirement of a secondary 
procedure. Therefore, the primary objective is to determine if intra-pyloric botulinum toxin 
injection during a minimally invasive esophagectomy decreases postoperative occurrence of 
delayed gastric emptying. The primary outcome is delayed gastric emptying (assessed 
radiographically by nuclear medicine emptying study) which is treated as a dichotomous variable.
Patients will be stratified by receipt of neoadjuvant chemoradiotherapy, smoking status, and 
diabetes; and randomized in a 1:1 to the botulinum and non-botulinum treatment arms. The 
primary objective will be assessed using the intent-to-treat principle and a one-sided Cochran-
Mantel-Haenszel (CMH) s test about the following hypotheses:
,
𝐻0:θ ≥1 
𝐻𝐴:θ < 1
where θ is the common odds ratio (COR) for the odds of delayed gastric emptying rates for the 
botulinum versus non-botulinum treatment arms. A one-sided test is performed as the rate of 
delayed gastric emptying is expected to decrease in the botulinum arm over the non-botulinum 
arm; that is, we expect θ < 1. 
The analysis will proceed in two stages using an O’Brien-Fleming alpha spending function. An 
interim analysis will be conducted after n1=30 patients have completed treatment and the final 
analysis will be conducted after n=50 patients have completed treatment. The following decision 
rules will be utilized at each analysis:
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Analysis
Decision Rule
Interim

If p-value ≤ 0.011396, then reject H0 and stop due to superiority.

If 
, then stop due to inferiority.
θ > 1

Otherwise enroll n2=20 patients.
Final

Reject H0 if p-value ≤ 0.046533
Secondary Analysis: The secondary outcomes include additional postop procedures, clinically 
assessed delayed gastric emptying (days to resumption of oral feeding, EORTC QLQ-30 QoL 
scores, and clinical symptoms of regurgitation, vomiting, and aspiration), delayed gastric emptying 
assessed by the gastrografin swallow exam/CT esophagram, pulmonary complications (aspiration, 
respiratory failure requiring reintubation, pneumonia within 3 months of surgery), and hospital 
length of stay. All variables will be reported by treatment arm using the appropriate descriptive 
statistics and graphical summaries.
The days to resumption of oral feeding, QoL scores and, hospital length of stay will be compared 
between treatment arms using the two sided independent-sample, stratified T-test. Normality will 
be assessed using the Anderson-Darling test and transformations (such as Box-Cox) will be 
applied, as appropriate. Bootstrap or non-parametric methods will be applied if no normalizing 
transformations can easily be applied. The rates of moderate clinical delayed gastric emptying 
(clinical signs of regurgitation, vomiting, and aspiration), moderate delayed gastric emptying 
(score of 2 or 3 on the gastrografin swallow test/CT esophagram), severe delayed gastric emptying 
(score of 4 or 5 on the gastrografin swallow test/CT esophagram), and pulmonary complications 
will be compared between treatment arms using the two-sided CMH exact test.
A previous study demonstrated that the rate of additional postoperative procedures may be lower 
for patients treated with botulinum (3.9%) as compared to those without botulinum (15.9%). 
Therefore, the rates of additional postop procedures within 3 months of the original procedure will 
be compared between treatment arms using a one-sided CMH exact test.
All analyses will be performed in SAS v9 (Cary, NC).
9.4.1
Adverse Events
The adverse events will be reported by grade using frequencies and relative frequencies. 
Additionally, the study will be monitored by the RPCI Data and Safety Monitoring Committee, 
which will assess the progress of the study, the safety data, and critical efficacy endpoints.
9.5
Interim Analysis and Criteria for Early Termination of the Study
An interim analysis will be conducted after n1=30 patients have completed treatment and will 
consider the following decision rules:
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Analysis Decision Rule
Interim
1. If p-value ≤ 0.011396, then reject H0 and stop due to 
superiority.
2. If 
, then stop due to inferiority.
θ > 1
3. Otherwise enroll n2=20 patients
10 ETHICAL AND REGULATORY STANDARDS
10.1 Ethical Principles
This study will not be initiated until the protocol and informed consent document(s) have been 
reviewed and approved by a properly constituted Institutional Review Board (IRB) or Independent 
Ethics Committee (IEC). Each participant (or legal guardian) shall read, understand, and sign an 
instrument of informed consent prior to performance of any study-specific procedure. It is the 
responsibility of the investigator to ensure that the participant is made aware of the investigational 
nature of the treatment and that informed consent is given.
The Investigator is responsible for the retention of the participant log and participant records; 
although personal information may be reviewed by authorized persons, that information will be 
treated as strictly confidential and will not be made publicly available. The investigator is also 
responsible for obtaining participant authorization to access medical records and other applicable 
study specific information according to Health Insurance Portability and Accountability Act 
regulations (where applicable).
This study will be conducted in compliance with all applicable laws and regulations of the state 
and/or country and institution where the participant is treated. The clinical trial should be 
conducted in accordance with the ethical principles embodied in the Belmont Report: Ethical 
Principles and Guidelines for the Protection of Human Subjects of Research, consistent with good 
clinical practice and the applicable regulatory requirements and according to the guidelines in this 
protocol, including attached appendices.
10.2 Informed Consent
The Investigator (or IRB specified designee) is responsible for obtaining written consent from each 
participant or the participant's legally authorized representative in accordance with GCP guidelines 
using the approved informed consent form, before any study specific procedures (including 
screening procedures) are performed. The informed consent form acknowledges all information 
that must be given to the participant according to applicable GCP guidelines, including the purpose 
and nature of the study, the expected efficacy and possible side effects of the treatment(s), and 
specifying that refusal to participate will not influence further options for therapy. Any additional 
information that is applicable to the study must also be included. Additional national or 
institutionally mandated requirements for informed consent must also be adhered to. The 
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participant should also be made aware that by signing the consent form, processing of sensitive 
clinical trial data and transfer to other countries for further processing is allowed.
The Investigator shall provide a copy of the signed consent form to the participant and the signed 
original shall be maintained in the Investigator File. A copy of the signed consent form must be 
filed in the participant file. At any stage, the participant may withdraw from the study and such a 
decision will not affect any further treatment options.
11 STUDY RESPONSIBILITIES
11.1 Data Collection
Data entry into the REDCap database is to be completed in a timely fashion (within 30 days) after 
the participant’s clinic visit. If an AE is considered serious it is captured on the Serious Adverse 
Event Source Form, which is handled in an expedited fashion.
Data management activities are performed using a CTMS system that enables the collection, 
cleaning and viewing of clinical trial data. eCRF data will be collected in REDCap, but Adverse 
Event data will be collected in Advarra EDC for DSMC reporting.
11.2 Maintenance of Study Documents
Essential documents will be retained per RPCI’s policy for 6 years from the study termination 
date. These documents could be retained for a longer period, however, if required by the applicable 
local regulatory requirements or by an agreement with RPCI.
12 ADMINISTRATIVE RULES
12.1 Revisions to the Protocol
RPCI may make such changes to the protocol as it deems necessary for safety reasons or as may 
be required by the U.S. FDA or other regulatory agencies. Revisions will be submitted to the 
IRB/ERC for written approval before implementation.
12.2 Termination of the Study
It is agreed that, for reasonable cause, either the RPCI Investigators or the Sponsor, may terminate 
this study, provided a written notice is submitted within the time period provided for in the Clinical 
Trial Agreement. In addition, RPCI may terminate the study at any time upon immediate notice if 
it believes termination is necessary for the safety of participants enrolled in the study.
12.3 Confidentiality
Any data, specimens, forms, reports, video recordings, and other records that leave the site will be 
identified only by a participant identification number (Participant ID, PID) to maintain 
confidentiality. All records will be kept in a limited access environment. All computer entry and 
networking programs will be done using PIDs only. Information will not be released without 
written authorization of the participant.
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13 APPENDICES
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Appendix A
ECOG Performance Status Scores
Description
Status
Fully active, able to carry on all pre-disease performance without restriction.
0
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light 
or sedentary nature, e.g., light housework, office work.
1
Ambulatory and capable of all self-care but unable to carry out any work activities.
2
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours.
3
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair.
4
Dead
5
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Appendix B
Ineligible Pharmacologic Agents 

Daily use of medications that delay or enhance gastric emptying:

Prokinetic agents, including erythromycin, metoclopramide, tegaserod, domperidone

Anticholinergic 
antispasmodic 
agents, 
including: 
dicyclomine, 
hyoscyamine, 
glycopyrrolate

Other agents, including atropine, nifedipine, progesterone, octreotide, theophylline, 
benzodiazepine, phentolamine, opioids
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Appendix C
Nuclear Medicine Questionnaire 
1. Did you have trouble eating the entire meal within the time allotted?
2. Did you have trouble eating the solid component?
3. Did you experience acid indigestion or heartburn at any point during the study?
4. Did you experience nausea or reflux at any point during the study?
5. Did you vomit at any point during the study?
6. Did you have pain related to eating at any point during the study?
7. Did you feel too full at any point during the study?
8. What medications did you take in the past 48 hours (2 days)?
________________
Patient Signature: ____________________________________________ Date: ________
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Appendix D
EORTC QLQ- OES18
Patient Signature: ____________________________________________ Date: ________
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Appendix E
Pre-Procedure Instruction Handout for Patients:
Your doctor has ordered a test that will permit evaluation of how food moves through your new 
stomach conduit. This test is called a Nuclear Medicine Gastric Emptying Study. This study will 
be performed in the nuclear medicine department.
Preparation for the Gastric Emptying Study:

You should not consume any liquids or food after midnight the night before the test. You 
should turn off your jejunal tube feeds at midnight as well.

If you smoke, do not smoke any time after midnight and throughout the time you are 
having the study pictures recorded. You may smoke after you are instructed that the test 
is completed.

Some medications are stopped for this test. This should be discussed with your doctor. 
The following medications must be stopped for 48 hours (2 days) before the test: Reglan 
(metoclopramide), erythromycin, benzodiazepines (Ativan, Valium, Xanax), and opioids 
(Lortab, Norco, Percocet, Dilaudid, Methadone, Morphine, Oxycontin, Oxycodone). Do 
not take any laxatives on the day before or any time during your study.

Unless otherwise directed by your physician, you may continue your normal medications 
that could be taken with a small amount of water or juice up to 2 hours prior to your 
study. You should not drink coffee or tea.

If you have diabetes, skipping breakfast may affect your need for diabetic medication. If 
you are a diabetic and on insulin, we request that you bring your regular morning dose of 
insulin with you. You can take this with the meal that will be given to you. We may 
reduce your insulin dose to adjust for the small size of the breakfast. Often half of your 
insulin is taken with the test meal. If you take oral hypoglycemic medications, generally 
these are taken with the meal in the nuclear medicine department. If there are any 
questions concerning your dose of insulin this should be discussed with your study 
coordinator or surgeon.

If you have diabetes, we also ask you to bring your glucose monitoring equipment to the 
test. We will ask you to check your glucose before the test and possibly during or after 
the test.
Description of the Gastric Emptying Study:

For this test, you will be asked to eat an egg meal that consists of the equivalent of 
one egg together with water. The meal has been labeled with an isotope that will 
permit pictures to be taken as the meal passes through the stomach conduit.

Pictures of short duration are acquired with you standing in front of the nuclear 
medicine department’s gamma camera. Between the images you will be permitted to 
walk about and continue normal activities. It is suggested that you bring some reading 
material and/or personal music device. These studies try to simulate normal daily 
activities. The nuclear medicine department’s rooms may be cooler than the rest of 
the hospital, and you may want to bring a sweater with you.

The study generally takes 4 hours once it is started.
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Roswell Park Cancer Institute Study Number: I 283516
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
12/03/21
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Roswell Park Cancer Institute Study Number: I 283516
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
12/03/21
Page 46 of 46
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