Clinical trial NCT00941655
Conditions: Gastric Cancer
Keywords: Gastric Carcinoma Chemotherapy Liver Tumors Peritoneal Tumors Metastatic Gastric Cancer Stomach Cancer Gastric Cancer
Sponsor: National Cancer Institute (NCI)
Start date: 2009-07-22; Completion date: 2012-06-18
Enrollment: 15 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Background:

* Gastric (stomach) cancer is a rare cancer. In most cases, by the time it has been diagnosed it has spread to other organs in the body and the chance of a cure is very small. The standard treatment for gastric cancer is a combination of chemotherapy drugs.
* Researchers are interested in finding out if surgically removing all tumors before beginning chemotherapy for stomach cancer can slow or halt its spread better than giving chemotherapy alone.

Objectives:

\- To determine whether tumor removal surgery followed by chemotherapy is more effective in treating gastric cancer than chemotherapy given alone.

Eligibility:

\- Patients 18 years of age and older who have been diagnosed with gastric cancer.

Design:

* All patients will undergo an initial physical examination, blood tests, imaging scans, and a laparoscopy to determine the extent of the disease.
* Half of the participants will be assigned to have surgery first and then chemotherapy; the other half will be assigned to have chemotherapy alone.

  * The surgery-plus-chemotherapy group will have major surgery to remove all tumors in the stomach and abdominal area, followed by a recovery time of up to 4 weeks. Chemotherapy will begin 6 to 8 weeks after surgery.
  * The chemotherapy-only group will begin treatment within 2 weeks of laparoscopy.
* All patients will receive four chemotherapy drugs: 5-Fluorouracil, leucovorin, oxaliplatin, and irinotecan. The drugs are given intravenously over 2 days every 2 weeks (one cycle) for 12 cycles (about 6 months), either at the National Institutes of Health (NIH) Clinical Center or at home with a referring oncologist. Patients in the surgery group who have tumors in the peritoneum will receive an additional set of chemotherapy drugs in a separate treatment.
* During the chemotherapy cycles, patients will provide blood samples approximately once a week and will have physical examinations and scans on a regular basis.
* Patients will return to the NIH Clinical Center for follow-up visits about every 4 months for 2 years, then every 6 months for 3 years and yearly thereafter.

Detailed description:
Background:

* The standard of care for metastatic gastric cancer (MGC) is systemic therapy resulting in median survival of 6-12 months and rare survivors of up to three years.
* For patients with limited MGC, retrospective studies have shown improved overall survival following gastrectomy and/or metastasectomy plus systemic therapy (e.g. median survival after liver resection for metastatic gastric cancer of 15-37 months, with a five year survival rate of 25%).
* This prospective randomized trial for patients with MGC and limited metastases is designed to compare two therapeutic approaches-gastrectomy with metastasectomy plus systemic therapy (GYMS) vs. systemic therapy alone (SA)-- and to evaluate outcome in light of selection criteria to define those patients who may benefit from the more aggressive approach.

Objectives:

Primary Objective:

\- To compare two therapeutic approaches--GYMS vs. SA--in terms of overall survival in patients with limited MGC.

Secondary Objectives:

* To analyze selection criteria for patients who might benefit from the GYMS approach.
* To determine progression-free survival in both arms.

Eligibility:

* MGC with limited metastatic disease thought to be resectable to no evidence of disease.
* 18 years old or greater with an Eastern Cooperative Oncology Group (ECOG) 0-2
* Laboratory and physical examination parameters within acceptable limits by standard of practice guidelines prior to surgery

Design:

* Patients will be randomized to receive gastrectomy and metastasectomy followed by systemic chemotherapy (GYMS) or systemic chemotherapy (SA) alone and will be stratified based on sites of metastatic disease, previous therapy and disease free interval.
* Patients in both arms will receive the FOLFOXIRI regimen (5-FU, leucovorin, oxaliplatin and irinotecan)
* No cross over will be allowed.
* Survival analysis will be done in intention to treat fashion from time of randomization.
* Based on estimated 12 and 20 months overall survival for the SA and the GYMS arms respectively, 68 patients per arm (power=0.80, 0.05 two-tailed log-rank test) will be enrolled. Patients will be recruited over 6 years and followed for an additional 2 years from the date of entry of the last patient.

Arms: arm 1: Surgery -gastric resection, metastasectomy, and heated intraperitoneal chemotherapy with Fluouracil (5-FU) 400 mg/m\^2 intravenous (IV) over 5 minutes. Leucovorin 20 mg/m\^2 IV and Oxaliplatin 460 mg/m\^2 diluted in 2.0 L/m\^2 of dextrose 5% in water (D5W) given as a heated intraperitoneal perfusion.

Systemic chemotherapy - Irinotecan 165 mg/m\^2 IV over 90 minutes, Oxaliplatin 85 mg/m\^2 over 120 minutes, Leucovorin 200 mg/m\^2 IV 120 minutes, 5FU 3200 mg/m\^2 continuous IV infusion over 48 hours. arm 2: Irinotecan 165 mg/m\^2 IV over 90 minutes, Oxaliplatin 85 mg/m\^2 over 120 minutes, Leucovorin 200 mg/m\^2 IV 120 minutes, 5FU 3200 mg/m\^2 continuous IV infusion over 48 hours.
Interventions: intervention 1: Oxaliplatin intervention 2: Irinotecan intervention 3: 5-Fluorouracil intervention 4: Leucovorin intervention 5: Gastrectomy and/or metastasectomy
Intervention descriptions: intervention 1: Oxaliplatin 460 mg/m\^2 diluted in 2.0 L/m\^2 of dextrose 5% in water (D5W) given as a heated intraperitoneal perfusion.

Systemic chemotherapy - Oxaliplatin 85 mg/m\^2 over 120 minutes, intervention 2: Irinotecan 165 mg/m\^2 IV over 90 minutes intervention 3: Surgery and heated intraperitoneal chemotherapy with Fluouracil (5-FU) 400 mg/m\^2 intravenous (IV) over 5 minutes.

systemic chemotherapy -3200 mg/m\^2 continuous intravenous over 48 hours. intervention 4: surgery and heated intraperitoneal chemotherapy -20 mg/m\^2 intravenous over 5 minutes.

systemic chemotherapy - 200 mg/m\^2 intravenous over 120 minutes. intervention 5: Gastrectomy: tumor resection and a bypass; palliative treatment for pain, bleeding, obstruction and/or if deemed in the best interest of the patient.

Metastasectomy: anatomical segmental resection to render the patient no evidence of disease (NED) with at least 1cm negative margins when possible, followed by systemic chemotherapy.

Protocol documents:
Prot_SAP_000.pdf: 
Abbreviated Title: Metastatic Gastric Cancer 
 
  
 
CC Protocol Number: 09-C-0189 G 
Prospective Randomized Trial Comparing Gastrectomy, Metastasectomy plus Systemic 
Therapy versus Systemic Therapy Alone: GYMSSA Trial
Principal Investigator:  
Udo Rudloff, M.D., PhD1
Lead Associate Investigator: Prakash Pandalai, M.D.1
Associate Investigators:  
Udai S. Kammula, M.D.1
David Schrump, M.D.1
 
 
 
 
King Kwong, M.D.1
Austin Duffy, M.D.2
Daniel Zlott, PharmD4
Martha Quezado, M.D.3
Aradhana Venkatesan, M.D.5
Melissa Walker, R.N.1
Carole Webb, R.N.1  
 
 
 
Mary Ann Toomey, R.N.1 
 
 
 
 
 
 
 
Seth M. Steinberg, Ph.D.6
1Surgery Branch, CCR, NCI 
2Medical Oncology Branch, CCR, NCI 
3Laboratory of Pathology, CCR, NCI 
4NIH Clinical Center Pharmacy 
5Diagnostic Radiology Department, NIH Clinical Center 
6Biostatistics and Data Management Section, CCR, NCI 
Version Date: May 17, 2012 
Date of Submission: May 29, 2009


09-C-0189 
 
 2 
PRECIS
Background:
x
The standard of care for metastatic gastric cancer (MGC) is systemic therapy resulting in 
median survival of 6-12 months and rare survivors of up to three years.  
x
For patients with limited MGC, retrospective studies have shown improved overall 
survival following gastrectomy and/or metastasectomy plus systemic therapy (e.g. 
median survival after liver resection for metastatic gastric cancer of 15-37 months, with a 
five year survival rate of 25%).
x
This prospective randomized trial for patients with MGC and limited metastases is 
designed to compare two therapeutic approaches: gastrectomy with metastasectomy plus 
systemic therapy (GYMS) vs. systemic therapy alone (SA) and to evaluate outcome in 
light of selection criteria to define those patients who may benefit from the more 
aggressive approach. 
Objectives:
Primary Objective:
x
To compare two therapeutic approaches: GYMS vs. SA in terms of overall survival in 
patients with limited MGC.  
Secondary Objectives:
x
To analyze selection criteria for patients who might benefit from the GYMS 
approach.
x
To determine progression-free survival in both arms. 
Eligibility: 
x
MGC with limited metastatic disease thought to be resectable to no evidence of 
disease. 
x
18 years old or greater with an  ECOG 0-2 
x
Laboratory and physical examination parameters within acceptable limits by standard 
of practice guidelines prior to surgery 
Design:
x
Patients will be randomized to receive gastrectomy and metastasectomy followed by 
systemic chemotherapy (GYMS) or systemic chemotherapy (SA) alone and will be 
stratified based on sites of metastatic disease, previous therapy and disease free 
interval (Appendix 3, trial schema). 
x
Patients in both arms will receive the  FOLFOXIRI regimen (5-FU, leucovorin, 
oxaliplatin and irinotecan)
x
No cross over will be allowed. 
x
Survival analysis will be done in intention to treat fashion from time of 
randomization. 
x
Based on estimated 12 and 20 months overall survival for the SA and the GYMS 
arms respectively, 68 patients per arm (power=0.80, 0.05 two-tailed log-rank test) 
will be enrolled. Patients will be recruited over 6 years and followed for an additional 
2 years from the date of entry of the last patient.  


09-C-0189 
 
 3 
Table of Contents 
1.
Introduction: ......................................................................................................................... 4
1.1.
Study Objectives ............................................................................................................. 4
1.2.
Background and Rationale ............................................................................................ 4
2.
Eligibility Assessment and Enrollment: ............................................................................ 10
2.1.
Eligibility Criteria ........................................................................................................ 10
2.2.
Research Eligibility Evaluation................................................................................... 12
2.3.
Patient Registration, Stratification, and Randomization ......................................... 14
3.
Study Implementation: ....................................................................................................... 15
3.1.
Staging Laparoscopy .................................................................................................... 16
3.2.
Gastrectomy, Metastasectomy, Peritonectomy and Intraperitoneal Therapy ....... 16
3.3.
Intraperitoneal Chemotherapy CHPP ....................................................................... 20
3.4.
Postoperative Care ....................................................................................................... 21
3.5.
Systemic Chemotherapy Therapy............................................................................... 22
3.6.
Treatment Evaluation During Chemotherapy: ......................................................... 24
3.7.
Evaluation of Response and QOL Assessment .......................................................... 24
3.8.
Off Treatment Criteria ................................................................................................ 25
3.9.
Post Treatment Follow up (Both Arms) ..................................................................... 25
3.10.
Off Study Criteria ..................................................................................................... 25
3.11.
Measurement of Health Related Quality of Life .............................................. 26
4.
Supportive Care: ................................................................................................................. 27
5.
Data Collection and Evaluation:........................................................................................ 28
5.1.
Data Collection ............................................................................................................. 28
5.2.
Response Criteria ......................................................................................................... 28
5.3.
Toxicity Criteria ........................................................................................................... 29
5.4.
Statistical Section.......................................................................................................... 30
5.5.
Safety and Monitoring Plan ........................................................................................ 31
5.6.
Clinical Trial Monitoring Plan .................................................................................... 32
6.
Human Subject Protection: ................................................................................................ 32
6.1.
Rational for Subject Selection ..................................................................................... 32
6.2.
Evaluation of Potential Benefits and Risks ................................................................ 33
6.3.
Risks/Benefit Analysis .................................................................................................. 33
6.4.
Consent Process ............................................................................................................ 33
7.
Data Reporting: ..................................................................................................................... 34
7.1.
DEFINITIONS ............................................................................................................... 34
7.2.
Routine Data Reporting ............................................................................................... 35
7.3.
Exclusions to Routine Data Reporting: ...................................................................... 36
7.4.
NCI-IRB REPORTING.................................................................................................. 37
8.
Pharmaceutical Information: ............................................................................................ 37
8.1.
Oxaliplatin..................................................................................................................... 37
8.2.
Leucovorin Calcium (Injection) .................................................................................. 38
8.3.
5-Fluorouracil ............................................................................................................... 39
8.4.
Irinotecan ...................................................................................................................... 40
9.
References: ........................................................................................................................... 42
10.
Figures, Tables and Appendices ..................................................................................... 48


09-C-0189 
 
 4 
1. Introduction:
1.1. Study Objectives
1.1.1. Primary Objective: 
x
To determine whether a therapeutic approach that includes gastrectomy and/or 
metastasectomy plus systemic therapy is superior to the standard of care 
approach that includes systemic therapy alone in terms of overall survival for 
patients who present with limited metastatic gastric cancer (MGC). 
1.1.2. Secondary Objectives:
x
To compare progression-free survival (PFS) between the two study arms 
x
To analyze prognostic factors and generate potential selection criteria for 
patients who present with limited gastric cancer metastases that might benefit 
from gastrectomy and/or metastasectomy plus systemic therapy. 
x
To analyze prognostic factors and generate potential selection criteria for 
patients who present with limited gastric cancer metastases that will not 
benefit from gastrectomy and/or metastasectomy.  
x
To determine if surgical resection impacts the dosing and duration of 
subsequent chemotherapy administration 
x
To compare quality of life (QOL) parameters between the two study groups. 
We will use tools specifically developed for assessment of QOL in gastric 
cancer patients: FACT-Ga, EORTC QLQ-STO22 and the SROTC QLQ-C301-
4.
x
To determine and compare patterns of disease recurrence between the two 
therapeutic approaches and their clinical implications.  
1.2. Background and Rationale
 
Gastric cancer is the fourth most common cancer world-wide with approximately 
930,000 people diagnosed each year and an annual mortality close to 700,0005.  In the 
United States, in 2008 approximately, 21,500 people will develop gastric cancer and an 
estimated 10,880 individuals will die from the disease6.   Overall, gastric cancer is the 
14th most common cancer in the United States, and accounts for 1.5% of all new 
diagnoses and 5.2% of all cancer deaths6.   The annual age-adjusted incidence rate is 8 in 
100,000 with an annual death rate of 4.1 in 100,0007.  The lifetime risk for developing 
gastric cancer is 0.89% or 1 in 113 men and women born in the United States today7.  At 
the time of diagnosis,  4-14%  of patients will present with metastases to the liver 8,9,10
and 0.1% with metastases to the lung45, 46. At the time of initial surgical intervention for 
locally advanced disease,15-50%   of patients will  have metastases to the peritoneum38
This study seeks to define the role of  metastasectomy in patients with gastric cancer who 
present with metastases to the liver, peritoneum, or lung.  


09-C-0189 
 
 5 
Hepatic Disease 
At the time of diagnosis 35% of patients present with evidence of distant 
metastases with 4-14% having metastatic disease to the liver 8,9,10.  A study from 
Memorial Sloan-Kettering Cancer Center (MSKCC) described patterns of recurrence in 
completely resected gastric adenocarcinomas (NED) in a large series of patients (n=1172) 
and found liver specific recurrence rates at 37%11.  In a study analyzing 643 patients 
enrolled in 5 separate chemotherapy trials by the Japanese Clinical Oncology Group, 
(JCOG) 5-year survival for patients with liver only metastases treated with systemic 
therapy alone was 1.7%12.  There have been no large prospective studies detailing the 
natural history of metastatic gastric carcinomas and long term survival.  However, two 
small randomized trials compared best supportive care with combination chemotherapy 
and found that no patients treated with supportive care lived for longer than 1 year 13,14,15.
Palliative chemotherapy has been widely used as the treatment of choice, but only 
minimal improvements have been observed with median survival increasing from 3 
months to 7-12 months13-17.
Over the past several decades, hepatic resections have evolved into a common 
operative procedure performed safely at large centers throughout the world.  
Improvements in the understanding of anatomy, physiology, perioperative care, and 
surgical technique have reduced operative mortality for liver resections to less than 4%18.
In most tertiary referral cancer centers, liver resection carries mortality of less than 2%.  
For hepatic colorectal metastases, retrospective studies spanning thousands of patients 
show that surgical resection can yield 5-year survival between 35 – 62 %19.  Similar 
results have been observed following resection of hepatic metastases from primary 
neuroendocrine tumors with resection now considered the standard treatment.  Initial 
reports of liver resections for metastatic gastric cancers have been encouraging but are 
limited by being retrospective and consisting of only a small number of patients.   
Resection of liver metastases from gastric cancer is not widely performed; 
however a thorough review of the literature (Kerkar and Avital et al., in preparation) 
identified 19 studies reporting survival rates on a total of 358 patients receiving hepatic 
resections for gastric adenocarcinomas.  The in-hospital mortality rate was 3.7%.  Median 
overall survival for the reporting studies was 18 months and median 5-year actuarial 
survival was 24.5% (range: 0 -60%).  Although follow up was limited in several studies, 
13.4% of patients were still alive at 5 years (Table 1).   The presumed aggressive biology, 
high incidence of peritoneal dissemination, and lack of sufficient data from single studies 
reporting on patients undergoing metastasectomy for metastatic gastric cancer to the liver 
have made it difficult to highlight the benefits of operative management for these 
patients. 
Although the data certainly represents a highly selected group of patients and bias 
of surgeons, evidence that long term survival can be achieved in individuals with 
metastatic gastric cancer to the liver is nonetheless encouraging.  Furthermore, analyzing 
the characteristics of individuals surviving for greater than 5 years  shows that potential 
‘cures’ exist, as evidenced by 7 (4%) patients living for greater than 10 years (Table 2).     


09-C-0189 
 
 6 
Patient selection is critical when considering liver resection but delineating 
conclusive prognostic factors from several retrospective studies may be less than ideal. 
Analyzing the data presented in these studies may help in identifying factors that can be 
prospectively analyzed in a clinical trial such as this.  Prognostic factors identified as 
being significant on univariate analysis in at least one study included the number of liver 
metastases (solitary vs. multiple nodules), negative resection margins, synchronous vs. 
metachronous presentation, certain primary tumor characteristics such as depth (serosal 
invasion), venous and lymphatic invasion, histologic grade, lymphocytic infiltration and 
fibrous pseudocapsule along with metastatic tumor characteristics such as disease free 
interval, size and distribution of metastases (unilobar vs. bilobar).  Factors identified as 
significant on multivariate analysis in at least one study included the number of liver 
metastases (solitary vs. multiple), negative resection margins, serosal/lymphatic/venous 
invasion of primary tumor, and synchronous vs. metachronous presentation.  Although 
two studies did show a significantly worse outcome for patients undergoing synchronous 
hepatic resections, the detailed analysis of 29 long term survivors shows that 17 patients 
(59%) had synchronous disease.
Considering the pattern of distant failure of gastric metastases, we believe that the 
majority of the study population will include patients with hepatic gastric metastases. 
Based on the data presented here regarding liver resection for hepatic gastric metastases 
and data from colorectal cancer metastatic to the liver, we propose the following selection 
criteria for this trial:  Patients eligible for this trial may include patients with synchronous 
or metachronous gastric liver metastases, and liver disease (bilateral or unilateral) limited 
to  5 lesions and/or  15cm.  
Peritoneal Disease 
The next most common mode of failure is locoregional-peritoneal disease. 
Sugarbaker et al. categorized gastric peritoneal disease into four distinct categories 
defined below37:
Peritoneal Staging (adapted with modifications)
P0
No peritoneal seeding 
P1
Adjacent peritoneal involvement only; seeding limited to the 
upper abdomen only, all resectable to  0.5mm
P2
Few scattered metastases to distant peritoneum; small-
volume seeding throughout the abdomen, resectable to 
0.5mm  
P3
Extensive peritoneal spread or not resectable to  0.5mm 
 
Patterns of failure after curative resection showed that up to 50% of patients 
undergoing gastric resection developed locoregional recurrences 1-3 years after surgery.  
There is a strong theoretical basis for the use of perioperative intraperitoneal 
chemotherapy with debulking to NED. The tumor cell entrapment hypothesis suggests 
that manipulation of the primary tumor at surgery result in free peritoneal cancer cells 
(Figure 1). These cells become fixed in fibrin and later results in peritoneal recurrence.  


09-C-0189 
 
 7 
This represents only one of several theoretical considerations. The use of adjuvant 
intraperitoneal chemotherapy for patients presenting with advanced primary gastric 
cancer has been examined in several randomized controlled trials (Table 3).  Individually, 
these trials were not powered to definitively highlight the role of adjuvant intraperitoneal 
chemotherapy. However, a meta-analysis in the Annals of Surgical Oncology in 2007 
concluded that patients with advanced gastric cancer treated with adjuvant hyperthermic 
intraoperative intraperitoneal chemotherapy experienced statistically improved overall 
survival38.
Another report in 2008 in the Journal of Surgical Oncology pooled together expert 
opinions for the interpretation of the previous randomized trials and meta-analysis in 
regard to intraoperative intraperitoneal chemotherapy as an adjuvant treatment 
modality39.  All the experts agreed that patients who have undergone a curative gastric 
resection and who have peritoneal washings with positive cytology should be treated with 
intraperitoneal chemotherapy.  Eighty-three percent recommended intraperitoneal 
chemotherapy for patients with T3 and T4 primary lesions39.  However, due to the 
heterogeneity of the randomized studies, a consensus for patient selection criteria and 
chemotherapy regimen still remains unclear.   
Patients who present with locally advanced disease are typically found to have 
peritoneal metastases during surgical exploration38 (15 -50%).  For these patients (with 
peritoneal dissemination resectable to no visible disease [NED] and no evidence of other 
distant metastases) the majority of the experts (83%) recommended peritonectomy 
followed by hyperthermic intraoperative intraperitoneal chemotherapy, although 92% of 
the experts believed a large randomized trial needed to be conducted to make this 
treatment standard of care39.
A large percentage (31%) of the patients with gastric cancer in the United States 
presents with stage IV disease, including P1-P2 disease. After analyzing 20 years of data 
from multiple studies of patients receiving a ‘palliative’ gastric resection for stage IV 
gastric cancer with peritoneal dissemination, Sugarbaker et al. concluded that gastric 
resection in the presence of peritoneal metastases improved  quality of life and survival37.
Furthermore, 4 separate small studies concluded that complete removal of both the 
gastric primary and all visible peritoneal disease combined with intraperitoneal 
chemotherapy was associated with improved survival40-43. For patients not treated with 
intraperitoneal chemotherapy, Ouchi et al. showed that overall survival was improved 
with total gastrectomy performed for patients with peritoneal disease44.  However, they 
also reported that patients with >P2 disease had significantly worse outcomes compared 
to those with P0 or P1 metastases. Patients with >P2 disease are excluded from this study. 
Therefore, based on the data presented regarding gastric peritoneal disease, we 
propose the following eligibility criteria: Patients with gastric peritoneal metastases of 
P2 disease, synchronous or metachronous, limited extrabdominal disease and disease 
resectable to NED.


09-C-0189 
 
 8 
Pulmonary Disease 
The incidence of lung metastases from gastric cancer is reported to be extremely 
low.  Kanemitsu et al. reported an incidence of 0.1% (4/3076)45, 46.  The following 
represents the sum of our knowledge regarding lung metastases from gastric cancer: Once 
considered the sine qua non for surgically unresectable disease, advances in anesthesia, 
thoracic surgery, and postoperative care have made pulmonary metastasectomies for 
other intestinal malignancies such as colorectal cancer an essential part of treatment of 
metastatic disease.  A review of over 5,000 patients who underwent pulmonary resections 
for malignancies of various histologies showed that after complete metastasectomy long 
term survival of 36% at 5 years, 26% at 10 years, and 22% at 15 years are possible in 
selected patients47.  Despite these promising but biased statistics, pulmonary resection of 
malignant gastric metastases is not routine.  Autopsy series of patients with gastric cancer 
demonstrate pulmonary metastases in 22-52% of patients45,48.  The incidence of clinically 
apparent pulmonary metastases ranges from 0.5-14%45,49.  Anywhere from 0.3-6% of 
patients will have purely isolated pulmonary metastases from their primary gastric 
adenocarcinoma45,49.  Pulmonary metastases treated with chemotherapy alone have 
traditionally been associated with poor outcomes, with survival measured in a few 
months50.
A thorough review of the literature identified case reports and several limited case 
series which report on 45 patients who have undergone resection of pulmonary 
metastases following curative resections of primary gastric malignancies (Kemp and 
Avital et al51, in preparation) (Table 4).  Resections included wedge excisions, segmental 
resections, and lobectomies.  No patients underwent pneumonectomy.  Mean survival in 
case series is 13.8-24.3 months45,52.  Several authors report survival of greater than 5 
years and one study reported on a long term survivor alive 7 years after metastasectomy 
53-56.  This translates into overall survival up to 15 years from the initial resection of the 
primary gastric cancer54.  In addition, repeated pulmonary resections, combinations of 
pulmonary and hepatic and pulmonary and adrenal lesions, as well as resection of 
primary lung cancer along with metastatic gastric cancer have all been reported, with 
long term survival a possibility in selected patients50,54,55,57,58.
Despite these promising reports of long term survival among highly selected 
patients who undergo resection of  pulmonary metastases from gastric cancer, 
metastasectomy has not been scientifically studied as a potential routine practice in the 
management of this disease.  Furthermore, no studies have adequately addressed this 
topic in a prospective, randomized fashion comparing metastasectomy to best alternative 
care of systemic chemotherapy. While considering the retrospective nature, inherent 
biases and limited experience from these studies, clearly there is a potential group of 
highly selected patients that might benefit significantly from aggressive approach to 
pulmonary gastric metastases. This study is designed to answer the question: What are 
the characteristics of patients who might benefit from the GYMS approach for metastatic 
gastric cancer, including metastases to the lung. 
The rational for using FOLFOXIRI in this trial:


09-C-0189 
 
 9 
Metastatic gastric cancer remains a therapeutic challenge due to poor prognosis 
and optimum chemotherapy regimen for this disease has not been established.  Several 
randomized phase III trials comparing combination chemotherapy such as 5-fluorouracyl 
(5-FU), doxorubicin, and mitomycin or 5-FU, doxorubicin and high dose methotrexate 
with best supportive care have demonstrated significantly prolonged overall  survival 
(OS) of 8-10 months for chemotherapy group as compared with 3-5 months in the best 
supportive care alone group59,60.  Since then, various combination chemotherapy 
regimens were tested in phase II or phase III trials in metastatic gastric cancer without 
significant improvement in overall survival. A recent phase III trial comparing docetaxel-
cisplatin-5-FU (DCF) to the reference arm of cisplatin-5FU (CF) showed a modest 
improvement in OS (9.2 vs. 8.6 months), time to progression (5.6 vs. 3.7 months), and 
response rate (37% vs. 25%) for the DCF arm61. These results represent one of the best 
improvements in treatment of metastatic gastric cancer. However, DCF was associated 
with high rates of grade 3 and 4 toxicities, and as a consequence the regimen has not yet 
been widely accepted. 
Irinotecan, a camptothecin analog, acts as an anti-tumor agent by inhibiting the 
eukaryotic enzyme DNA topoisomerase I. Irinotecan has demonstrated high activity as a 
monotherapy in gastric cancer patients with response rates from 18% to 43%62,63. Phase II 
studies with irinotecan plus 5-FU and leucovorin (FOLFIRI) showed a response rate of 
40% with median survival time between 10.7 and 12.6 months64-66.  A phase II study of 
modified FOLFIRI in gastric cancer patients who had failed taxane/cisplatin 
chemotherapy reported a response rate of 21% with low toxicity profile67.
Oxaliplatin, an alkylating agent, inhibits DNA replication by forming DNA adducts 
between two adjacent guanines or guanine and adenine molecules. Oxaliplatin has shown 
a notable activity against colorectal cancer in combination with 5-FU and leucovorin, 
which has led to several phase II trials in gastric cancer. The oxaliplatin/5-FU/leucovorin 
regimen yielded response rates in the range of 38% to 54% with a survival time from 8 to 
11 months with favorable toxicity profile68.
 In an attempt to develop a more active and efficacious chemotherapy regimen, irinotecan 
and oxaliplatin, have been combined with or without 5-FU and leucovorin in a few phase 
I trials, which have shown safe toxicity profiles in patients with advanced solid tumors69.
Preclinical studies reported synergistic anti-tumor activities between irinotecan and 
oxaliplatin in several tumor cell lines70.  A phase II study of irinotecan, oxaliplatin plus 
continuous infusion of 5-FU/leucovorin without chronomodulation in 32 colorectal 
cancer patients produced very promising activity with a response rate of 72%71. Another 
phase II study of FOLFIRINOX in advanced pancreatic cancer patients also yielded 
response rate of 26% with manageable toxicity72.
On the basis of these encouraging results, several phase II studies were recently 
executed in order to assess the efficacy and safety of the modified FOLFOXIRI as a 
frontline chemotherapy in patients with metastatic gastric cancer73,74.  Results from these 
trials are among the best ever reported in gastric cancer: Overall response rate of 63-66% 


09-C-0189 
 
 10 
(CR 2-4% and PR 60-65%), median survival 12-15 months, and median time to 
progression 7-10 months. The most common grade 3/4 toxicities were: neutropenia (12-
49% of all cycles), emesis (8-42% of all cycles), grade 2 neuropathy (10%), grade 3 
diarrhea (10%), and stomatitis (4%). No grade 4 non-hematologic toxicities were 
observed.
The role of surgery in early and/or locoregional solid organ cancers is relatively 
well defined. When solid organ cancers, including gastrointestinal cancers, are diagnosed 
in an early stage and found to be resectable to NED, surgical resection with or without 
adjuvant systemic therapy can result in high cure rates. However, the role of surgery in 
patients with metastatic solid organ cancers continues to be controversial. Generally, the 
alternative, systemic therapy, on average, achieves only a single digit improvement in 
median survival and five year survivors are rare with few exceptions. In some cancers, 
such as colorectal, sarcoma, endocrine and breast cancers with metastases to the liver and 
the lung, metastasectomy is relatively an acceptable practice in specialty centers. 
Although considered “systemic disease”, in selected patients, surgery plus systemic 
therapy resulted in dual digit 5-year survivals. This practice is not based on prospective 
randomized trials but instead on multiple retrospective reports. It took >30 years to 
compile enough retrospective data to establish these practices, i.e. liver and lung 
resection for colorectal and neuroendocrine cancers. As a strategy for the next 5 to 7 
years, one of the aims the Surgery Branch is to ask the following question in a scientific 
fashion: What is the role of surgery plus systemic therapy in metastatic gastrointestinal 
and breast cancers? This study is the first trial resulting from this strategy. 
In light of the retrospective data presented here suggesting that metastasectomy 
plus systemic therapy might improve outcomes in metastatic gastric cancer, the purpose 
of the current study (the GYMSSA Trial) is to answer the question: What is the role of 
surgery plus systemic therapy in patients with gastric cancer who present with limited 
metastases to the liver, lung and peritoneum (P2 disease).  In addition, we will be 
monitoring the safety of this combined modality treatment in light of previously 
conducted studies 80, 81. The study will be conducted as a random-assignment phase III 
trial. After thorough staging, including laparoscopy and peritoneal washings, patients will 
be stratified and randomized to one of two arms: GYMS (gastrectomy and/or 
metastasectomy plus systemic therapy) vs. SA (systemic therapy alone.) The primary 
objective is to define the overall survival in the two study groups. Importantly, this study 
will try to define the characteristics of patients with gastric metastases who might benefit 
from gastrectomy and/or metastasectomy plus systemic therapy. The Surgery Branch in 
collaboration with the Medical Oncology Branch of the NCI aim to answer these 
questions in a scientific manner.  
2. Eligibility Assessment and Enrollment:
2.1. Eligibility Criteria
2.1.1.
Inclusion Criteria


09-C-0189 
 
 11 
a.
Histologically or cytologically confirmed gastric adenocarcinoma  
b.
Metastatic disease must be measurable by CT and/or MRI  
or
There must be a history of positive peritoneal washings or carcinomatosis 
c.
All disease should be deemed resectable to negative margins (NED) based 
on imaging studies e.g.: 
x
Esophageal invasion <4cm that does not require thoracotomy  (Seiwert 
II and III lesions) 
x
Hepatic metastases (unilateral or bilateral  d 5 lesions, d 15 cm total 
diameter) 
x
Primary peritoneal metastases (small disease load d P2 disease) 
without massive ascites or intestinal obstruction 
x
Para-aortic lymph node metastases (stations 16 a1 and/or b2, see 
appendix 5) 
x
Lung metastases (d3 unilateral/bilateral, 9 cm total diameter) 
x
Patients who present with both hepatic and peritoneal metastases must 
have no evidence of extensive para-aortic/retro-pancreatic lymph node 
metastases 
Note: Patients with both pulmonary and peritoneal metastases will be 
enrolled at the discretion of the PI 
d.
Greater than or equal to 18 years of age 
e.
Must be able to understand and sign the Informed Consent Document 
f.
Clinical performance status of ECOG d2
g.
Life expectancy of greater than three months 
h.
Patients of both genders must be willing to practice birth control during 
and for four months after receiving chemotherapy 
i.
Hematology: 
x
Absolute neutrophil count greater than 1500/mm3 without the support 
of Filgrastim. 
x
Platelet count greater than 75,000/mm3.
x
Hemoglobin greater than 8.0 g/dl. 
j.
Chemistry: 
x
Serum ALT/AST less or equal to 5 times the upper limit of normal; 
except in the presence of obstructive liver metastases where ALT/AST 
may be up to 10 times the upper limit of normal 
x
Serum creatinine less than or equal to 1.5 mg/dl unless the measured 
creatinine clearance is greater than 60 mL/min/1.73 m2
x
Total bilirubin less than or equal to 2 mg/dl, except in the presence of 
obstructive metastases   
x
PT within 2 seconds  of the upper limit of normal (INRd1.8)
k.
No history of prior/other malignancies within the 2 years prior to 
enrollment with the exception of basal cell carcinoma 
2.1.2.
Exclusion Criteria 
a.
Prior treatment with FOLFOXIRI (treatment with any of the components 
as separate regimens is allowable) 


09-C-0189 
 
 12 
b.
Inability to tolerate any of the chemotherapeutic agents 
c.
Grade 2 or greater neuropathy 
d.
Women of child-bearing potential who are pregnant or breastfeeding 
because of the potentially dangerous effects of the chemotherapy on the 
fetus or infant. 
e.
Active systemic infections, coagulation disorders or other major medical 
illnesses of the cardiovascular, respiratory or immune system, myocardial 
infarction, cardiac arrhythmias, obstructive or restrictive pulmonary 
disease. 
f.
Brain metastases or a history of brain metastases 
g.
Childs B or C cirrhosis or with evidence of severe portal hypertension by 
history, endoscopy, or radiologic studies 
h.
Weight less than 40 kg 
i.
Significant ascites, greater than 1000cc in the absence of peritoneal 
disease
j.
History of congestive heart failure and/or an LVEF < 40%  
Note: Patients at increased risk for coronary artery disease or cardiac 
dysfunction (e.g., >65yo, diabetes, history of hypertension, elevated LDL, 
first degree relative with coronary artery disease) will undergo full cardiac 
evaluation and will not be eligible if they demonstrate significant 
irreversible ischemia on stress thallium or an ejection fraction <40%. 
k.
Significant COPD or other chronic pulmonary restrictive disease with 
PFT’s indicating an FEV1 less than  50% or a DLCO less than 40% 
predicted for age
Note: Patients who have shortness of breath with minimal exertion or who 
are at risk for pulmonary disease (e.g., chronic smokers) will undergo 
pulmonary function testing and will not be eligible if their FEV1 is < 50% 
of expected. 
l.
Concomitant medical problems that would place the patient at an 
unacceptable risk for a major surgical procedure or for the administration 
of FOLFOXIRI 
2.2. Research Eligibility Evaluation
2.2.1. Within 6 weeks prior to treatment: 
x
Complete physical examination including vital signs, height and weight as 
well as ECOG assessment.
x
HIV, Hepatitis B surface antigen and Hepatitis C antibody 
x
UGT1A1genotyping (selected patients)
x
12 lead EKG 
x
Patients will undergo pulmonary function tests as indicated in section 
2.1.2 i.
x
Cardiac evaluation with possible stress test for patients with history of 
cardiac disease will be performed as indicated in section 2.1.2h
x
Thoracic oncology consult for patients with pulmonary metastatases
x
Pathology will be confirmed by the NCI Laboratory of Pathology.


09-C-0189 
 
 13 
x
Radionuclide bone scan, when clinically indicated.
x
MRI Brain when indicated.
x
PET-CT when indicated.
x
EGD-EUS when indicated.
x
Female patients will undergo pelvic ultrasound and/or MRI if indicated.
2.2.2. Within 4 weeks prior to treatment: 
x
Baseline imaging: CT scan of chest, abdomen and pelvis (CT C/A/P) with 
triphasic 1mm cuts as per the liver scan protocol.  For patients with 
evidence of hepatic disease, a baseline MRI-L will be performed.  Note: If 
the screening CT and MRI of the liver are consistent indicating that CT is 
an accurate reflection of hepatic disease, then CT may be used for baseline 
and subsequent evaluations. 
x
Randomization (Note: patients should begin treatment as soon as feasible 
following randomization) 
x
Helicobacter pylori IgG Antibody 
x
Patients who test positive for H. pylori will receive: 
o
Omeprazole 20 mg po  daily x 10 days 
o
Clarithromycin 500 mg po  twice daily x 10 days 
o
Amoxicillin 1000mg po twice daily x 10 days 
 OR 
o
Omeprazole 20 mg po daily x 10 days 
o
Clarithromycin 500 mg po twice daily x 10 days 
o
Metronidazole 500 mg po twice daily x 10 days 
2.2.3. Within 3 – 6  weeks prior to treatment (one week prior to randomization): 
All patients will have a definitive staging laparoscopy and peritoneal 
washings. Pathology results of peritoneal washings must be completed 
before randomization. (Note: patient should be randomized as soon as 
feasible following laparoscopy)
2.2.4. Within 2 weeks prior to treatment: 
x
Laboratory evaluation
o
CBC with platelets 
o
Chem-20 (Sodium (Na), Potassium (K), Chloride (Cl), total CO2 
(bicarbonate), Creatinine, Glucose, Urea nitrogen (BUN), Albumin, 
Calcium total, Magnesium total (Mg), Inorganic Phosphorus, 
Alkaline Phosphatase, ALT/GPT, AST/GOT, Total Bilirubin, 
Direct Bilirubin, LD, Total Protein, total CK, Uric acid 
o
Ferritin, Prealbumin, 
o
PT/PTT & INR,
o
Urinalysis 
o
iron levels, B12 levels, c-reactive-protein 
o
tumor markers (CEA, CA19-9, AFP, CRP, CA 15-3, CA 27-29 and 
CA125)


09-C-0189 
 
 14 
x
Anesthesia consult – for patients randomized to the surgery arm 
2.2.5. Within 2-3 days prior to chemotherapy 
x
Complete physical examination including vital sign measurements, weight 
and ECOG assessment should be conducted within 3 days prior to 
treatment.  This can be performed by home oncologist if patient decides to 
undergo systemic therapy at home. 
x
Serum beta-HCG on all females of child bearing potential or urine 
pregnancy test within 2 days prior to treatment. 
2.2.6. On Study within 1 week of surgical treatment: 
x
Physical examination including vital sign measurements, weight and 
ECOG assessment.  
x
Laboratory evaluation: CBC, platelets, Chem-20 (Sodium (Na), 
Potassium (K), Chloride (Cl), total CO2 (bicarbonate), Creatinine, 
Glucose, Urea nitrogen (BUN), 
Albumin, Calcium total, Magnesium total (Mg), 
Inorganic Phosphorus, Alkaline Phosphatase, ALT/GPT, AST/GOT, 
Total Bilirubin, Direct Bilirubin, LD, Total Protein, total CK, Uric 
acid, PT/PTT & INR, Urinalysis. 
x
Base line tumor markers, Prealbumin and Ferritin. 
2.3. Patient Registration, Stratification, and Randomization
Registration of patients onto this study will take place within 10 days of the patient 
signing the consent by faxing a completed eligibility checklist to the Central 
Registration Office (CRO) at 301-480-0757 between 9:00 and 5:00 Monday through 
Friday.  Following laparoscopy, patients will be stratified and then randomized by the 
CRO to receive gastrectomy and/or metastasectomy plus systemic therapy (GYMS arm) 
or standard therapy (SA arm).  The CRO will notify the Study Coordinator of the results 
of randomization.   
Note:  As soon as the patient has signed the informed consent, the patient’s referring 
oncologist (or Dr Duffy or his designee for those patients being treated at the NCI) will 
be notified of the expected date of randomization and potential start dates for the 
chemotherapy.  Immediately following randomization the referring oncologist will be 
notified.  Subjects who are randomized to receive chemotherapy only must begin 
chemotherapy treatment within 14 days following randomization.
Stratification will be done according to the following factors:  
x Site of metastases (liver, lung, and peritoneal disease). Note: positive peritoneal 
washings will be stratified as peritoneal disease. 
x Time to development of first metastases (earlier than 1 year vs. later than 1 year) 
x Previous systemic therapy specifically given for gastric metastases vs. no therapy 
for metastatic disease.  (Note: patients who have received adjuvant chemotherapy 
will be stratified to the no therapy for metastatic disease group)


09-C-0189 
 
 15 
3. Study Implementation:
Study Design (See appendix 3 for trial schema) 
Experimental Design:
x
This is a prospective randomized trial comparing the effects of two therapeutic 
approaches, gastrectomy and/or metastasectomy plus systemic therapy (GYMS) to 
systemic therapy alone (SA) on the overall survival of patients with limited gastric cancer 
metastases. 
x
Patients who are newly diagnosed as well as those who have received prior systemic 
treatment for gastric metastases will be eligible.  Both groups will be randomized to 
surgery plus chemotherapy or chemotherapy alone.  
x
Candidate patients for this trial will undergo all or part of the following staging elements 
before randomization and/or if indicated medically: pathologic confirmation of gastric 
cancer as feasible, H&P, laboratory evaluations, imaging studies and other studies as 
medically indicated.   
x
Patients who enroll and are willing to have tissue collected for research purposes will be 
enrolled on protocol 09-C-0079.
x
All patients found eligible will undergo staging laparoscopy with peritoneal lavage prior 
to randomization.  
x
Patients will be randomized following staging laparoscopy and after the results of the 
peritoneal washings are available.  
x
Stratification will adjust for site of metastases (liver, peritoneal and lung), disease-free 
interval (DFI), and previous systemic therapy for gastric metastases. Note: positive 
peritoneal washings will be stratified as peritoneal disease. 
x
Patients randomized to the GYMS approach and who have peritoneal disease will 
undergo, as an integral part of their treatment, complete peritonectomy and peritoneal 
perfusion (CHPP).  
x
Patients who present with intrabdominal disease without peritoneal involvement will 
undergo CHPP with limited peritonectomy as described in section 3.2.6 
x
All patients randomized to the GYMS arm will undergo gastrectomy, modified D2 lymph 
node dissection and/or appropriate metastasectomy followed by systemic therapy.  
x
H. pylori infection will be tested and treated following the recommendations of the 
American College of Gastroenterology guideline on the management of H. pylori
infection75 (Appendix 2).  This treatment should not delay surgery. 
x
Patients randomized to the systemic therapy arm (SA) will receive systemic therapy 
preferably by their home medical oncologist or by the NCI Medical Oncology Branch.  
x
Systemic therapy: Since there is no definitive standard of care in metastatic gastric cancer 
and oxaliplatin and/or irinotecan were shown in phase III trials76 to be equally effective to 
other common regimens in gastric cancer, patients will receive the FOLFOXIRI regimen 
as described by Masi et al from the GONO group77.
x
Patients in the SA arm who develop metastases synchronous to the primary gastric cancer 
will be eligible for palliative gastrectomy for pain, bleeding, obstruction and/or if deemed 
in the best interests of the patients. 
x
Palliative gastrectomy will include tumor resection (R0 when possible) and a bypass. As 
per standard of care, no adjacent organ resection (with the exception of obstructing 
lesions) will be performed.  


09-C-0189 
 
 16 
x
During follow up, all patients will undergo H&P laboratory evaluation and imaging 
studies and tumor markers as indicated. The timing of all follow up evaluations will be 
based on the date of randomization.   
x
Progression will be measured by a radiologist blinded as to the treatment arm.  
3.1. Staging Laparoscopy
3.1.1.      Patients who meet eligibility criteria will be taken to the operating room for 
staging laparoscopy and peritoneal washings. At laparoscopy biopsies of the 
peritoneum will be done and used later to confirm status of peritoneal disease 
(not as a part of the staging procedure but as part of the study).
x
Any suspicious lesions that might preclude resection to NED will be 
biopsied as well.  
x
Liver ultrasound to confirm axial imaging findings will be done.  
x
Randomization and stratification will be done after laparoscopy and only 
after the results of the peritoneal washings are known (within one week of 
laparoscopy).
3.1.2.       Patients will then be randomized to receive gastrectomy and/or 
metastasectomy plus systemic therapy (GYMS arm) or systemic therapy 
alone (SA arm). 
x
Patients randomized to receive the standard of care (SA arm) will receive 
systemic therapy (as described in Section 3.5). Note: Patients may 
undergo palliative gastrectomy if indicated but must begin chemotherapy 
within 6 weeks of gastrectomy (8 weeks following randomization). 
x
Patients randomized to receive gastrectomy and/or metastasectomy plus 
systemic therapy (GYMS arm) will be taken to the operating room within 
1-2 weeks of randomization (as soon as feasible). Patients may undergo 
surgery only at the NCI. Subsequently, patients will receive systemic 
therapy within 4 to 16 weeks after surgery and/or when fully recovered 
from surgery. Patients who do not recover within 16 weeks will be taken 
off treatment and followed for survival. (Note: patients who undergo 
thoracotomy for pulmonary metastases must be able to receive systemic 
therapy within 24 weeks of their initial surgery.) This is an intent-to-treat 
phase III trial. 
3.2. Gastrectomy, Metastasectomy, Peritonectomy and Intraperitoneal Therapy  
Surgical Guidelines: 
Note: The following guidelines are for the purpose of promoting consistency in the 
surgical procedure, and peri-operative care where possible.  Physician discretion will be 
exercised as necessary to ensure that the specific needs of the patient are met.  Details 
pertaining to surgical and perioperative management will be recorded in the patient 
medical record but will not be captured on the CRFs.  
3.2.1. Preoperative Patient Management 


09-C-0189 
 
 17 
x
Patients will receive standard preoperative care as appropriate to the planned 
surgical intervention and the patient’s underlying health status which may 
include:
o
The day prior to surgery: anti-embolism stockings (TEDS), Sequential 
Compression Devices (SCDS), incentive spirometry and appropriate 
bowel preparation regimen
o
The night before operation: Hibiclens® shower 
Note: For patients undergoing hepatic resection, no anticoagulation will be given 
prior to operation.
3.2.2.  Patient Management in the Operating Room:
x
Patients will receive broad spectrum antibiotics in the recovery room before 
moving into the operating theater. 
x
Epidural catheters should be considered in all patients. Decisions will be made 
by the anesthesiologist and the operating surgeon in full collaboration. 
x
TEDS will be placed and SCDs will be “on” before induction of anesthesia.  
x
A central venous line, arterial line, and large bore catheters will be placed if 
blood loss is anticipated to be >500cc. 
x
In cases where liver resection is anticipated, fluid administration will be 
tightly coordinated with the operating surgeon. Before the liver parenchyma is 
transected administered crystalloids should be limited to <500ml when 
possible. During parenchymal transection the CVP should be kept under 4 and 
preferably at 0-1 using Trendelenburg position and vasodilators; urine output 
of 25 cc per hour will be considered sufficient.  
3.2.3. Choice of Gastric Resection: 
General Guidelines: 
x
The overall goal for surgical therapy is to render the patient NED and to 
obtain negative margins whenever technically feasible. 
x
All patients will receive an intraoperative ultrasound of the liver regardless of 
the preoperative imaging or laparoscopic ultrasound to determine if hepatic 
metastases exist even if preoperative imaging fails to show evidence of 
disease. 
x
Hand sewn anastomosis with PDS and a G-J tube placement for patients 
undergoing CHPP and gastrectomy will be preferred. 
x
A resection of surrounding organs will be allowed if the operating surgeon 
observes local invasion. 
x
The drainage procedure after gastric resections will consist of either a Billroth 
II or preferably, Roux-en-Y gastrojejunostomy when possible. 
Type of resection 
x
Lesions of the gastric body or antrum: a “radical subtotal gastrectomy” will be 
performed: this will include an approximate 70-90% distal gastrectomy, and if 
technically feasible, ligation of the right gastric, right gastroepiploic, and left 
gastric arteries at their origin with removal of associated lymphoid tissues.  
The lesser and greater omentum will be removed if considered resectable. 


09-C-0189 
 
 18 
x
Proximal lesions: a total gastrectomy with 2-4 cm esophageal margins will be 
done when possible. 
x
Lesions of the cardia or fundus: a total gastrectomy will be performed where 
possible.  Tumors extending < 4 cm into the esophagus will also be resected 
through the abdominal incision with the intention of gaining 2-4 cm negative 
margins on the esophagus. 
x
Distal lesions: a proximal subtotal gastrectomy (as opposed to total 
gastrectomy)  with high ligation of the left gastric artery, removal of the 
gastrosplenic ligament, lesser omentum and surrounding lymphoid tissue will 
be done when possible
3.2.4. Lymph node dissection:
x
Perigastric lymph nodes (stations 1, 3 and 5) and greater curvature lymph 
nodes (stations 2, 4 and 6) are grouped as N1 (D1 range); the nodes around the 
left gastric artery (station 7), common hepatic artery (station 8), celiac artery 
(station 9) and splenic artery (stations 10 and 11) are grouped as N2 (D2 
range). More distant nodes such as para-aortic nodes (N3 and N4) are 
regarded as distant disease (M1). 
x
All visible perigastric lymph nodes will be removed along with technically 
feasible resections of lymph nodes along the following named arteries: 1) 
Right Cardiac, 2) Left Cardiac, 3) Left Gastric, 4) Celiac, 5) Splenic Artery, 6) 
Hepatic Artery, 7) Suprapyloric, 8) Infrapyloric, 9) and low paraesophageal 
according to the extent of gastrectomy. 
x
A modified D2 lymph node resection will be carried out to include removal of 
the omental bursa along with the posterior leaf of the transverse mesocolon, 
anterior leaf covering the pancreas, and lymph node stations 1-11 without 
obligatory splenectomy or distal pancreatectomy. 
x
The extent of a D2 resection will be determined by the operating surgeon 
depending on tumor characteristics and whether nodal regions can be accessed 
safely while sparing the spleen and pancreas. However, if the tumor is 
adherent to the spleen or invading the gastrosplenic ligament, a splenectomy 
will be performed 
Note: Patients at risk for splenectomy (proximal T3-T4 lesions) may receive 
triple vaccination (Pneumococcal, Meningococcal, Haemophilus influenzae)
prior to surgery. 
3.2.5. Hepatic metastasectomy: 
x
Intraoperative ultrasound will be performed on all patients to detect disease 
not witnessed on preoperative imaging. Unexpected findings will be recorded 
in the patients chart. 
x
The goal of hepatic metastasectomy is to render the patient NED with at least 
1 cm negative margins when possible. 
x
The preferred modality of hepatic metastasectomy is anatomical segmental 
resection. For single lesions, when possible, segmentectomy should be 
performed. For more than a single isolated lesion, a secterectomy or partial 
hepatectomy should be performed if feasible. In all cases, the surgeon should 
strive to obtain negative margins.  


09-C-0189 
 
 19 
x
A non-anatomic wedge resection shall be performed only for small superficial 
lesions deemed resectable to negative margins by intra-operative ultrasound 
and preoperative imaging. 
x
In selected cases, intraoperative RFA and/or microwave ablation may be used 
at the discretion of the operating surgeons if deemed in the best interests of the 
patient.  
x
Portal vein ligation/embolization should be considered in selected patients to 
preserve post-operative liver function.
x
A formal hepatic lobectomy will be done for large lesions spanning more than 
two sectors, or multiple lesions within a single hepatic lobe. 
x
In all cases of hepatic gastric metastasis undergoing liver resection, the 
surgeon should perform portal and hepatic artery lymph node dissection 
whenever possible. 
3.2.6. Peritoneal metastasectomy (cytoreductive surgery):
x
If there is evidence that the extent of disease is beyond the ability to be 
debulked such that the largest residual tumor nodule is less than or equal to 
0.5 cm, patients will be considered ineligible and removed from treatment.   
x
For patients with primary peritoneal metastases (small disease load; P0-P2 
disease) without massive ascites or intestinal obstruction, all visible disease 
will be resected if technically feasible. 
x
Complete peritonectomy for patients with peritoneal disease includes the 
following: the right and left sub-diaphragmatic peritoneum, the falciform 
ligament, lesser and large omentum, anterior, right and left abdominal wall 
down to the paracolic gutters and the pelvic peritoneum. 
x
Partial (limited) peritonectomy for patients with intra-abdominal disease 
without peritoneal disease includes (i.e., liver metastases without peritoneal 
disease): peritoneal attachment of the hepatic left lateral segment and the 
spleen, 2 cm along the incision at the anterior abdominal wall and the 
falciform ligament (Appendix 1). 
3.2.7. Para-aortic lymph-node metastases:
x
To be considered eligible for CHPP and debulking with “positive” para-aortic 
lymph nodes, patients will have no evidence of metastatic disease outside of 
para-aortic lymph nodes on preoperative imaging and no evidence of hepatic 
or peritoneal metastases on intraoperative examination. 
x
Stations 16a1 and/ or b2 will be resected when technically possible. 
3.2.8. Lung metastases:
x
Timing of resection will be in the best interest of each individual patient. The 
decision will be made by the thoracic surgeon and the GI surgeon. It can 
either be performed at the same time as the gastric resection or at a later time 
point, with a delay of no more than 16 weeks in cases of synchronous disease. 
Note: patients must begin chemotherapy within 24 weeks of randomization. 
x
Lung metastasectomy will follow the standard of care and as defined by the 
inclusion/exclusion criteria. 


09-C-0189 
 
 20 
3.3. Intraperitoneal Chemotherapy CHPP
3.3.1. Perfusion 
x
Two large bore catheters will be inserted through the abdominal wall, one 
over the right lobe of the liver and one in the pelvis.  The abdominal fascia 
will be closed, and the catheters connected to a perfusion circuit.   
x
The perfusate passes from a reservoir through a roller pump, heat exchanger, 
and then into the abdominal cavity.
x
Efflux from a second catheter is then recirculated through the reservoir and 
pump.   
x
The perfusion flow rate will be maintained at 2.0 L/min and a perfusate 
volume will be maintained which moderately distends the abdominal cavity 
correlating with intra abdominal pressures of 5 to 15 mm Hg (2.0 L/m2).
Stable perfusion parameters are obtained and the peritoneal cavity is warmed 
to a minimum of 41q C prior to starting the clock for perfusion time.   
x
The perfusion will be continued for 35 minutes.   
x
During the perfusion, constant physical manipulation of the abdomen 
(shaking) will be maintained for the entire 35 minutes to assure even 
distribution of the perfusate. 
x
The heater coil will be maintained at 46-48°C.  Peritoneal temperature will be 
measured continuously by three probes placed immediately beneath the 
peritoneal surface on either side of the abdomen and in the pelvis.   
x
The patient’s core temperature will be measured with an esophageal probe 
(which correlates well with pulmonary artery temperatures) and maintained at 
less than 41°C using a cooling blanket and ice packs around the legs and head.   
x
At the end of the perfusion, the abdomen will be re-opened and the perfusate 
irrigated from the abdominal cavity. 
3.3.2. Medications 
All intraperitoneal drug dosages will be calculated on ideal body weight (IBW).  
Ideal body weight will be calculated based upon the following formula: 
IBW (male, in kg) =  {(Height in inches – 60) x 2.3} + 50 
IBW (female, in kg) = {(Height in inches – 60) x 2.3} + 45.5 
x 5-FU  (patients randomized to surgery arm) 
Due to pH incompatibility, 5-FU cannot be mixed with oxaliplatin inside the 
peritoneal cavity; therefore, it will be administered IV, to bath the tumor and 
healthy tissue to potentiate oxaliplatin activity.  Prior to the beginning of 
CHPP patients will receive: 
o
Fluorouracil (5-FU) 400 mg/m2 IV  in 50 cc  over 5 minutes 
o
Leucovorin 20 mg/m2 IV  in 50 cc  over 5 minutes 


09-C-0189 
 
 21 
x Oxaliplatin (patients randomized to surgery arm) 
o
Oxaliplatin 460 mg/m2 diluted in 2.0 L/m2 of D5W via the perfusion circuit 
3.4. Postoperative Care
3.4.1. Patient Monitoring
x
The patients will be monitored in the Intensive Care Unit for no less than 12 
hours after surgical resection.
o
Routine ICU monitoring of vital signs will be performed according to 
the patient’s clinical status.  
o
While in the ICU, an attempt to keep urine output greater than 100 
cc/hour will be made when physiologically feasible.  
o
Patients will be transfused as appropriate to maintain a hemoglobin 
greater  than or equal to 8.0 g/dl, and platelet count greater than  
25,000 mm3
x
Patients will be discharged from the ICU at the discretion of the treating 
surgeon and in accordance with the institution policies.  
x
Following discharge from the ICU, vital signs (blood pressure, temperature, 
pulse, respirations) will be taken per routine (every 2-6 hours and as clinically 
indicated).
3.4.2. Continued Postoperative Management:
x
Patients will receive routine postoperative care; early ambulation will be 
encouraged. 
x
Laboratory evaluations will include: 
o
CBC, platelets, and acute panel daily x 4 days and then every third day or 
as clinically indicated until discharge.  
o
Tumor markers for new baseline will be obtained on the day of discharge.  
x
Patients undergoing CHPP who develop post operative thrombocytopenia and 
neutropenia will receive standard supportive care as needed. 
x
X-rays and scans as clinically indicated. 
3.4.3. Discharge:  
x
Total hospitalization may be approximately 7-21 days.   
x
Patients who are discharged within this time frame should be able to tolerate 
an oral diet.  Patients who have a prolonged hospitalization but are able to 
tolerate a diet may be discharged with home rehab/physical therapy.  
x
Within 5 days prior to discharge the following tumor markers should be 
drawn: AFP, CEA, CRP, CA 19-9, CA 125, CA 15-3,  and CA 27-29 
3.4.4. Post Discharge 
x
Patients will have CBC with differential and Chem 20 drawn weekly until 
values are less than or equal to grade 2 or baseline.  This may be done through 
the patient’s referring physician with the results faxed to Dr. Rudloff or his 
designee.


09-C-0189 
 
 22 
x
Patients will return to clinic approximately 4-6 weeks following surgery for 
their 1st post operative visit.  Subsequent follow up is detailed in section 3.9. 
3.5. Systemic Chemotherapy Therapy 
3.5.1. Guidelines
Patients who randomize to receive systemic chemotherapy alone (SA) will begin 
treatment within 14 days of randomization; patients who undergo palliative 
gastrectomy will begin chemotherapy within 6-8 weeks of randomization.  
Patients who randomize to surgery plus chemotherapy (GYMS) will begin 
treatment approximately 6-8 weeks following surgery (24 weeks for patients 
requiring sequential thoracic and abdominal surgery). Note: patients must meet 
eligibility requirements prior to beginning chemotherapy.  Patients who do not 
recover from the surgical procedure within the stated timeframe will be removed 
from treatment and followed for survival.
Systemic therapy may be administered by the patient’s local oncologist in 
collaboration with the PI or at the NCI by the Medical Oncology Branch. 
Systemic therapy will follow the guidelines for the FOLFOXIRI regimen77.
Chemotherapy and supportive care will be administered in accordance with each 
institution’s policies for the administration of chemotherapeutic agents. 
During treatment, the treating oncologist will be asked to fax the following 
information (Appendix 8) to the research nurse (noted below) at the conclusion of 
every other cycle (4 weeks): 

chemotherapy administration sheets including dose reductions and 
reason for dose reduction 

laboratory test results 

other clinically relevant information  
The patient will be asked to maintain a diary to be faxed to the research nurse 
every 4 weeks: 
Melissa Walker RN 
301-451-6933
All systemic chemotherapy will be administered based on actual body weight if 
within 20% above or below the ideal body weight.  If actual weight is not within 
20% of ideal body weight, then ideal body weight will be used to calculate 
systemic chemotherapy doses. 
Ideal body weight will be calculated based upon the following formula: 
IBW (male, in kg) =  {(Height in inches – 60) x 2.3} + 50 
IBW (female, in kg) = {(Height in inches – 60) x 2.3} + 45.5 
3.5.2. Treatment Schedule FOLFOXIRI 


09-C-0189 
 
 23 
Systemic chemotherapy will be administered every other week (one treatment 
every 14 days), and repeated for 12 cycles (approximately 6 months).  Patients in 
the systemic chemotherapy alone (SA) arm who are responding may continue 
chemotherapy beyond 12 cycles at the discretion of the PI.  Refer to Section 8 for 
further administration guidelines. 
Day 1: Irinotecan will be administered IV over 90 minutes followed by leucovorin 
IV and oxaliplatin IV given concomitantly over 2 hours, followed by 5-FU given 
via continuous infusion (CIV) over 48 hours. 
Dose Level 
Agent
Starting Dose 
Dose level -1 
(25% reduction) 
Dose level -2 
(50% reduction) 
Irinotecan  
165mg/ m2 IV  
123 / m2 IV  
82 /m2 IV
Leucovorin 
200 mg/m2 IV  
200 m2 IV 
200 mg/m2 IV 
Oxaliplatin 
85 mg/m2IV  
63 mg/m2 IV 
42 mg/m2 IV 
5-FU  
3200 mg/m2 CIV 
2400 mg/m2 CIV 
1600 mg/m2 CIV 
3.5.3.   Treatment Modifications FOLFOXIRI 


09-C-0189 
 
 24 
Treatment will be continued for up to 12 cycles (4 cycles = 1 course) unless one of the 
following events occur: disease progression, unacceptable adverse effects, or withdrawal 
of patient consent.  Dose modification will be based on toxicity profiles and adverse 
effects based upon the National Cancer Institute Common Terminology Criteria for 
Adverse Events (CTCAE version 3.0). 
The dose levels for oxaliplatin, irinotecan, leucovorin and 5-FU are noted above; the 
dose modification table is attached as Appendix 4.  
NOTE: Patients for whom peripheral neuropathy would pose significant hardship (e.g., 
musicians, jewelers, dentists) may receive the standard FOLFIRI regimen as noted 
below.
FOLFIRI 
  
  
Agent
Starting Dose 
Dose level -1 
(25% 
reduction)
Dose level -2 - 
50% reduction 
Irinotecan  
180 mg/ m2 IV  150 / m2 IV  
120 /m2 IV
Leucovorin 
200 mg/m2 IV  
200 m2 IV 
200 mg/m2 IV 
5-FU bolus 
400 mg/m2IV  
320 mg/m2 IV 
240 mg/m2 IV 
5-FU infusion 
(over 46 hours ) 
2400 mg/m2
CIV
2000 mg/m2
CIV
1600 mg/m2 CIV 
Day 1: Irinotecan will be administered IV over 90 minutes followed by leucovorin IV 
over 2 hours followed by 5-FU bolus injection, followed by 5-FU given via continuous 
infusion (CIV) over 46 hours.  Dose reductions will follow appendix 4; all evaluations 
will follow the same schedule as outlined for FOLFOXIRI.   
3.6. Treatment Evaluation During Chemotherapy:   
x
Laboratory evaluation weekly or according to the standards of the treating 
physician, to include: CBC with differential and  Chem 20: (Sodium (Na), 
Potassium (K), Chloride (Cl), Total CO2 (bicarbonate), Creatinine, Glucose, 
Urea nitrogen (BUN), Albumin, Calcium total, Magnesium total (Mg), 
Inorganic Phosphorus, Alkaline Phosphatase, ALT/GPT, AST/GOT, Total 
Bilirubin, Direct Bilirubin, LD, Total Protein, Total CK, Uric Acid).   
x Physical examination and toxicity assessment every 2 weeks or according to  
     the standards of the treating physician 
3.7.
Evaluation of Response and QOL Assessment
x
CT scan of the chest/abdomen/pelvis will be performed within 4 weeks prior 
to the first chemotherapy treatment and then every 8 weeks (+/- 1 week) 
during chemotherapy (at the end of each course).   
x Response will be determined using RECIST criteria 
x Quality of Life Questionnaires as described in Section 3.11. 


09-C-0189 
 
 25 
3.8. Off Treatment Criteria   
x Completion of systemic chemotherapy regimen 
x Voluntary withdrawal from treatment  
x Inability to follow the treatment regimen 
x Unacceptable toxicity  
x Radiographic or clinical disease progression 
x Unwilling or unable to undergo surgical resection for progressive disease  
x If the physician deems it is in the patient’s best interest not to receive further 
treatment 
x Completion of chemotherapy
3.9. Post Treatment Follow up (Both Arms)
Patients will be evaluated every 12 weeks (+/- 2 weeks) for the first 2 years, following 
completion of chemotherapy, every 6 months for the next 3 years and yearly thereafter.  
At any stage between these follow-ups additional evaluations will be conducted as 
clinically indicated.  At each evaluation patients will undergo: 
x Physical examination 
x Laboratory tests to include CBC with differential and CHEM 20 
x Tumor markers as appropriate 
x CT scan of the chest, abdomen and pelvis and other imaging as appropriate 
x Completion of QOL measures  
Patients who are unwilling or unable to return for follow up evaluation will be followed 
by phone contact. The following information may be obtained: 
x Summary of treatment received  since the previous contact 
x Estimation of ECOG status 
x Request for imaging studies, physical exam and laboratory reports to be sent 
to the PI 
Note: The CT of chest/abdomen and pelvis, done within 2 weeks of randomization, will 
be used as the base line study for assessment of disease progression. In special cases 
MRI-L (liver MRI) will be used to assess liver disease or PET scan when indicated.  
Patients randomized to the GYMS arm who progress during the follow up period will be 
offered further debulking/metastasectomy if deemed in the best interest of the patient.  
No additional chemotherapy will be given as a part of this protocol; however, patients 
may be referred to other NCI treatment protocols or back to their treating oncologist. 
3.10.Off Study Criteria 
x
Death


09-C-0189 
 
 26 
x
Unwillingness to participate in study specified follow up (including phone 
contact)
x
If the physician deems it is no longer in the best interest of the patient to 
remain on study 
Note: As the objective of this study is overall survival, every attempt will be 
made to follow patients for life. 
 
Patients will be officially taken off study by contacting the CRO. 
3.11.Measurement of Health Related Quality of Life 
Baseline Quality of Life Questionnaires (QOL) will be completed prior to 
randomization, prior to cycle 9 of chemotherapy and then every 12 weeks (+/- 2 weeks) 
for the first 2 years, every 6 months for the next 3 years, and yearly thereafter. (Note: 
patients who begin chemotherapy >5 weeks following randomization will be asked to 
complete the QOL prior to the first cycle of chemotherapy. 
Patients will be informed of the details of the QOL part of this study and reassured that 
their decision to participate will not affect their participation in the either of the 
treatment arms of this protocol.  Once enrolled, the patient has the right at any time to 
elect not to continue completing the questionnaires.  In the event a patient goes off study 
prior to completion of the follow up time points, the data gathered from their completed 
QOL questionnaires will be included in the final analysis. 
To QOL parameters and quality of life adjusted survival between the two study groups, 
we will use tools specifically developed for assessment of QOL in gastric cancer 
patients: FACT-Ga, ; Blazeby JM, Eur J cancer 2004 (Appendix 6).  Measures will be 
initially administered by the Associate Investigator Research Nurse or designee prior to 
randomization.  The Research Nurse will assess the patient’s ability to read, and if the 
patient is unable to read, it will not be administered. The Research Nurse or designee 
will administer the questionnaires providing a firm surface at a table or a clipboard and 
a pencil.  The patients will be directed to complete the questionnaires using the 
following instructions: 
We would like to better understand how you and other persons in this study feel, how 
well you are able to do your usual activities, and how you rate your health while you 
are participating in this research study.  To help us better understand these things about 
you and other persons participating in this study, please complete these two 
questionnaires about your quality of life.  Both questionnaires should not take longer 
than 15 minutes to complete. 
The questionnaires are simple to fill out.  Be sure to read the instructions on the top 
each questionnaire.  Remember, this is not a test and there are no right or wrong 
answers.  Choose the response that best represents the way you feel.  I will quickly 
review the questionnaires when you are done to make sure that all the items have been 
completed.  Please answer all the items with the response that is most applicable.


09-C-0189 
 
 27 
You should answer these questions by yourself.  Your husband/wife or other family 
members or friends should NOT assist you in completing the questionnaires.  Please fill 
out the questionnaires now.  Return the questionnaires to me when you have completed 
them.  We will be asking you to complete these again during some of your follow up 
visits.  If you have any questions, please ask.
Once the patient has completed the questionnaires, the Research Nurse or designee, will 
review them for completeness and thank the patient for their cooperation.  Subsequent 
measurements will be administered by the Associate Investigator Research Nurse, or 
designee, when the patient returns for follow-up visits as specified in section 3.9. 
The Research Nurse or designee will request that the patient complete the questionnaires 
prior to seeing the physician, as the interaction between the patient and physician may 
influence the patient’s answers to the questionnaires. In the event a patient is taken off 
study, patients will be asked to complete one last set of questionnaires (as appropriate to 
the point of withdrawal) and the data will be included in the analysis.  Patients who are 
only being followed for length of survival will be asked to continue to participate in 
completing the measures at the set intervals (every 6-12 months) through the mail.  
Patients will be phoned prior to the scheduled date of measurement and asked to 
complete the questionnaire; the FACT-Ga will then be mailed to the patient with a self-
addressed return envelope and a cover letter with the script above as directions.  If the 
questionnaires are not returned within 2 weeks, patients are phoned again. 
4. Supportive Care:
During the post-operative period patients will receive all standard of care supportive 
measures including nasogastric tube drainage and bowel rest for ileus, pulmonary toilet 
teaching and incentive spirometry to prevent atelectasis, transfusions, and antibiotics as 
indicated.
During the administration of systemic chemotherapy patients will receive all necessary 
supportive care as per the guidelines of the treating physician and institution.  This may 
include:
x  
Blood transfusions and growth factor support as necessary for the 
management 
of 
myelosuppression. 
 
Filgrastim 
5 
mcg/kg/day 
subcutaneously may be administered for ANC less than 1000 mm3 or as 
per the guidelines of the treating institution.  Note: Filgrastim will not be 
administered prophylactically during systemic chemotherapy.   
x  
Neutropenic fever will be treated with broad-spectrum antibiotics pending 
culture results.  
x  
Renal dysfunction (very rare) from oxaliplatin will be managed with 
supportive measures such as avoidance of renal toxic drugs, maintenance 
of good renal perfusion (hydration), and diuretics as necessary.   
x  
Diarrhea will be managed with medication such as diphenoxylate/atropine 
or loperamide.   


09-C-0189 
 
 28 
x  
Mucositis will be treated with bicarbonate rinses or anesthetic mouth 
wash.
x  
Premedication with antiemetics, including 5-HT3 blockers with or without 
dexamethasone, is recommended during systemic chemotherapy. 
5. Data Collection and Evaluation:
5.1. Data Collection
Data will be collected using the NCI C3D web based data collection system.  Quality of 
life will be assessed using questionnaires as specified in section 3.11. 
5.2. Response Criteria
5.2.1. Surgery + chemotherapy arm 
Because of the nature of peritoneal imaging and because cytoreductive surgery will 
likely eliminate all imageable disease, response can only be measured in terms of 
radiographic or symptomatic disease-free survival and overall survival.  Patients will 
be followed with CT scans at predetermined intervals as described in Section 3.9.  At 
any time point when there is evidence of progressive disease (imageable tumor 
nodules or increasing ascites persistent on CT scans as interpreted by the official 
interpretation of the imaging studies) the patients will be scored as progressive 
disease.  In some cases this may require successive scans, but the time of recurrence 
will be retrospectively defined at the point the first scan demonstrated imageable 
disease.  Patients who have symptoms of peritoneal tumor recurrence will be 
followed closely with serial scans and where necessary, laparoscopy (GYMS arm) in 
order to confirm disease status.  
5.2.2. Systemic chemotherapy alone arm 
Lesions will be evaluated using the RECIST criteria as described below. 
Evaluation of target lesions*
x
Complete Response (CR):  Disappearance of all target lesions 
x
Partial Response (PR):  At least a 30% decrease in the sum of the longest 
diameter (LD) of target lesions taking as reference the baseline sum LD. 
x
Progression (PD):  At least a 20% increase in the sum of LD of target lesions 
taking as reference the smallest sum LD recorded since the treatment started 
or the appearance of one or more new lesions. 
x
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD taking as references the smallest sum 
LD. 
* 
All measurable lesions up to a maximum of 10 lesions representative of all involved 
organs should be identified as target lesions and recorded and measured at baseline.  Target 
lesions should be selected on the basis of their size (lesions with the longest diameter) and their 
suitability for accurate repetitive measurements (either by imaging techniques or clinically).  A 
sum of the longest diameter (LD) for all target lesions will be calculated and reported as the 
baseline sum LD.  The baseline sum LD will be used as reference to further characterize the 
objective tumor response of the measurable dimension of the disease. 
Evaluation of non-target lesions**


09-C-0189 
 
 29 
x
Complete Response (CR): Disappearance of all non-target lesions and 
normalization of tumor marker level. 
x
Non-Complete Response:  Persistence of one or more non-target lesions 
x
Progression (PD):  Appearance of one or more new lesions.  Unequivocal 
progression of existing non-target lesions 
** All other lesions (or sites of disease) should be identified as non-target lesions and should also be 
recorded at baseline.  Measurements are not required, and these lesions should be followed as 
“present” or “absent.” 
Evaluation of best overall response
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria. 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Confirmatory Measurement/Duration of Response Confirmation
To be assigned a status of PR or CR, changes in tumor measurements must be confirmed 
by repeat studies that should be performed at least 4 weeks after the criteria for response 
are first met. In the case of SD, follow-up measurements must have met the SD criteria at 
least once after study entry at a minimum interval of 6-8 weeks.
Duration of Overall Response
 
The duration of overall response is measured from the time measurement criteria are met 
for CR/PR (whichever is first recorded) until the first date that recurrent or progressive 
disease is objectively documented (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that recurrent disease is objectively documented.
Duration of Stable Disease
Stable disease is measured from the start of the treatment until the criteria for 
progression are met, taking as reference the smallest measurements recorded since the 
treatment started. 
5.3. Toxicity Criteria


09-C-0189 
 
 30 
 
 
This study will utilize the CTCAE version 3.0 for toxicity and adverse event 
reporting.  A copy of the CTCAE version 3.0 can be downloaded from the CTEP home 
page (http://ctep.info.nih.gov).  All appropriate treatment areas should have access to a 
copy of the CTCAE version 3.0. 
5.4. Statistical Section
 
The primary objective of the trial is to determine if there is a difference in overall 
survival among patients with limited gastric cancer metastases who are randomized to 
receive either systemic therapy alone or gastrectomy, metastasectomy and systemic 
therapy.
 
Based upon results in the literature, patients who would be eligible for this trial 
and who receive systemic therapy alone would be expected to have an estimated 12-
month median overall survival from the date of randomization. The goal of this study will 
be to determine if the use of gastrectomy, metastasectomy and systemic therapy will 
result in an 8-month increase in overall survival, to a median of 20 months.  Patients will 
be randomized between systemic therapy alone or gastrectomy, metastasectomy and 
systemic therapy and followed for overall survival.  Kaplan-Meier curves and a two-
tailed log-rank test will be the primary analysis methods. Assuming exponential overall 
survival curves, the hazard rate for the systemic therapy is 0.0578, or approximately a 
5.8% probability of death each month when the median survival is 12 months. If we 
assume that the surgery plus systemic therapy arm has a median overall  survival of 20 
months, this corresponds to a hazard rate of 0.0347, and the resulting hazard ratio for the 
comparison of the two overall survival curves would be 1.67. To compare these curves 
and detect a difference with a 0.05 two-tailed log-rank test, a total of 68 evaluable 
subjects per arm (136 total) will need to be enrolled over a 6-year period and followed for 
an additional 2 years from the date of entry of the last patient, with 121 total deaths, in 
order to have 80% power to compare the curves.  
 
Patients will be stratified for site of metastases (liver, peritoneal, or lung), disease-
free survival and prior systemic therapy for gastric metastases. 
 
Progression-free survival will also be evaluated using Kaplan-Meier curves, and a 
two-tailed log rank test, as a secondary endpoint. In addition, a prognostic factor 
evaluation using Cox proportional hazards modeling will take place after the study has 
concluded in order to identify if there are factors which can be identified that are 
associated with survival or progression free survival in patients randomized to treatments 
on this trial; this will also be interpreted as a secondary endpoint.
 
The study will be monitored by the NCI/CCR Data Safety and Monitoring Board 
on an annual basis to evaluate the safety of the two arms. The SAEs (typically grade 3 
toxicities, or greater) will be reported according to type of toxicity, and maximal grade 
noted per patient, for toxicities with at least a possible attribution to the therapy provided 
on that arm. Comparisons will be made between the two arms using Cochran-Armitage 
tests for trend, or other appropriate methods, to determine if there is increased toxicity 
associated with either arm.  


09-C-0189 
 
 31 
 
In addition, at the first Data Safety and Monitoring Board (DSMB) meeting held 
following the point at which half of the required total subjects have been enrolled (68 
total), a single evaluation for futility will be undertaken. Evaluations for better than 
expected efficacy will also be made annually, beginning after half the subjects have been 
enrolled. 
 
The futility evaluation will be performed as follows:  based on the full data 
available at the time, a conditional power analysis will be performed to determine if the 
trial is unlikely to find an effect at the 0.05 two-tailed significance level with continued 
accrual based on an overall survival endpoint. Median survivals of 12 and 20 months 
correspond to 12-month survivals of 50% and 66% respectively.  Using these as the 
values under the alternative, and using the actual proportions alive at 12 months, based on 
the observed fractions and the expected sample sizes at 12 months, the conditional power 
of the trial will be determined assuming accrual of the remaining patients to achieve a 
total of 136 patients. If the conditional probability of finding a difference at the two-sided 
0.05 level at the conclusion of the trial is less than 20%, then it will be reasonable to 
recommend that no further patients will be enrolled.  
 
The evaluation for better than expected efficacy will be performed as follows. 
Beginning at the first annual DSMB meeting after 68 patients have been randomized, 
annual interim evaluations will be performed to determine if there is sufficient evidence 
to terminate accrual because of a better than expected improvement in overall survival. 
An alpha spending function approach to monitoring will take place using an O’Brien-
Fleming interim evaluation boundary 79. It will be assumed that a total of 121 deaths 
would take place over a total of 8 years of accrual plus monitoring, and that monitoring 
would begin after approximately 40-45 deaths have been noted. The information fraction 
used to compute the interim boundary at each annual evaluation will be calculated as the 
number of patients who died /121.   
 
Quality of life evaluations will be compared between the two study arms, with 
comparisons at multiple individual time points, as well as with respect to changes from 
baseline. Wilcoxon rank sum tests will likely be used. The evaluation will be considered 
secondary, and p-values resulting from the analysis will be presented without adjustment 
for multiple comparisons, but in the context of the number of tests evaluated.  
 
It is expected that 24 patients per year can be accrued onto this trial, and thus 
accrual will be completed in approximately 6 years. Allowing for a very small number of 
inevaluable patients, the accrual ceiling will be set at 140 patients. 
5.5. Safety and Monitoring Plan
 
Careful evaluation to ascertain the toxicity and clinical response will be 
performed.  The principal investigator will monitor the data and toxicities to identify 
trends quarterly.  The principal investigator will be responsible for revising the protocol 
as needed to maintain safety.  The NCI IRB will review submitted adverse events 


09-C-0189 
 
 32 
monthly to also evaluate trends and will require a follow up plan from the principal 
investigator whenever a trend is identified. 
 
The trial will be monitored at least annually by the NCI/CCR DSMB.  Interim 
outcome results will not be revealed to the investigators of the trial; results will be 
presented to the investigators prior to final accrual to the trial only if the DSMB 
recommends early termination of the trial.  Until 68 patients have been randomized, only 
toxicity and adverse events will be examined at each review. Once 68 patients have been 
randomized, interim evaluations to determine whether there is sufficient evidence to 
terminate accrual because of a better than expected improvement in overall survival, will 
be performed as detailed in Section 5.4.  At the first such review of outcomes, a single 
evaluation for futility will also be performed.  
5.6. Clinical Trial Monitoring Plan
Harris Orkand Information Services (HOIS) provides study auditing/monitoring services 
under contract with the Center for Cancer Research, NCI.  The number of patient records 
monitored is based on actual accrual.  Below is a tabular summary of monitoring 
evaluations:
Time of year 
 
  
Evaluation 
# of records 
monitored 
%data
verification 
1st quarter 
(Jan.- March)  
Compare CRFs to source documentation, 
verify subject registration with Drug 
Accountability Records 
3-4 study 
patients 
100%
2nd quarter 
(April – June) 
Compare CRFs to source documentation, 
verify subject registration with Drug 
Accountability Records 
3-4 study 
patients
100%
3rd quarter 
(July – Sept.) 
Compare CRFs to source documentation, 
verify subject registration with Drug 
Accountability Records 
3-4 study 
patients
100%
4th quarter 
(Oct. – Dec.)  
Compare CRFs to source documentation, 
verify subject registration with Drug 
Accountability Records 
3-4 study 
patients
100%
            *Based on expected accrual, 25% of enrolled patients will be monitored. 
6. Human Subject Protection:
6.1. Rational for Subject Selection
The investigational nature and objectives of this trial, the procedure and the treatments 
involved, the attendant risks and discomforts, potential benefits and potential alternative 
therapies will be carefully explained to the patient in the clinic setting and in the hospital 
prior to treatment and prior to obtaining a signed Informed Consent. This is particularly 
important for this study because of the relatively unique nature by which the treatment is 
given.  That is to say, the patients must subject themselves to a major operative procedure 
with the attendant risks and complications associated with it in order to receive treatment 
without any assurance of benefit from the treatment. 


09-C-0189 
 
 33 
6.2. Evaluation of Potential Benefits and Risks
The potential benefit to patients undergoing this therapy would be palliation in terms of 
preventing or delaying intra-abdominal tumor progression and metastases elsewhere 
which can be a devastating and painful source of symptoms and cause for demise.  In 
addition, significant tumor response may extend progression free and overall survival.  
The risks for this protocol include the risks associated with any abdominal surgery. This 
includes postoperative bleeding, intra-abdominal infection, enterocutaneous fistulas, 
anesthetic mishap and perioperative death.  In addition, the toxicities of chemotherapy 
place the patients under risk.  A combination of surgery and chemotherapy may decrease 
healing at a time when healing of abdominal wounds and bowel anastomosis is essential 
for recovery.  All attempts will be made to avoid enterotomies or a bowel resection where 
feasible.  In the case of intraabdominal catastrophe after surgery, patients may require 
reoperation.
6.3. Risks/Benefit Analysis
Patients dying of peritoneal carcinomatosis suffer with recurrent bowel obstructions, 
nausea, vomiting, crampy abdominal pain and incapacitating ascites.  This clinical 
scenario justifies aggressive treatment strategies as a means of palliation and survival 
benefit.  In Phase I and II trials we have seen long-term remissions after CHPP in patients 
who were otherwise terminal with no other therapeutic options available.  
The potential benefit is great for these patients if a regional response is obtained.  
Therefore, this protocol involves greater than minimal risk, but presents the prospect of 
direct benefit to individual subjects.
6.4. Consent Process
All patients are thoroughly screened prior to initial consultation at the NIH.  This usually 
involves a telephone conversation between the patient and a physician or nurse associate 
investigator.  During the initial consultation the patient, along with family members, is 
presented a forthright and detailed overview of the treatment option available to them at 
the NIH.  The experimental nature of the treatment, its theoretical advantages and 
disadvantages, and an overview of the operative procedure and anticipated convalescence 
are presented.  The fact that the patient may undergo an operative procedure in order to 
receive therapy without any assurance of benefit, the aggressive nature of the treatment, 
and the likelihood of serious or potentially life-threatening complications are presented.  
The Informed Consent document is given to the patient and they are asked to review it, 
make notes and follow-up with a phone call to the physician or nurse investigator to have 
any additional questions answered prior to considering treatment on protocol. 
When the patient is admitted to the Clinical Center for treatment, an associate physician 
investigator responsible for the care of the patient presents the previously described 
information in detail. The research nurse or Principal Investigator, or designee is 
responsible for obtaining consent from the patient upon admission.  The patient is 
reassured that participation on the trial is entirely voluntary and that they can withdraw or 
decide against treatment at any time without adverse consequences.  In fact, the 


09-C-0189 
 
 34 
investigators assure the patient that if alternate therapies are preferred that we will do all 
that we can to facilitate obtaining consultation and treatment from the appropriate 
medical center.  The signed consent will be verified by the physician responsible for the 
care of the patient.  The patient is asked to participate in completing the self-administered 
questionnaires measuring health related quality of life during this study.  They are 
assured that their eligibility to participate in the perfusion portion of this study is not 
dependent upon their willingness to complete the quality of life questionnaires. 
7. Data Reporting:
7.1. DEFINITIONS
7.1.1. Adverse Event
An adverse event is defined as any reaction, side effect, or untoward event that occurs during 
the course of the clinical trial associated with the use of a drug in humans, whether or not the 
event is considered related to the treatment or clinically significant. For this study, AEs will 
include events reported by the patient, as well as clinically significant abnormal findings on 
physical examination or laboratory evaluation. A new illness, symptom, sign or clinically 
significant laboratory abnormality or worsening of a pre-existing condition or abnormality is 
considered an AE.  All AEs must be recorded on the AE case report form unless otherwise 
noted above in Section 6.1. 
All AEs, including clinically significant abnormal findings on laboratory evaluations, 
regardless of severity, will be followed until satisfactory resolution. AEs should be reported 
up to 30 days following the last dose of study drug.  AEs that are considered treatment 
related, expected, continuing, but not resolvable by 30 days after treatment completion (e.g., 
alopecia) will not be followed after the 30-day period.  
7.1.2. Suspected adverse reaction
Suspected adverse reaction means any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event. For the purposes of IND safety reporting, 
‘reasonable possibility’ means there is evidence to suggest a causal relationship between the 
drug and the adverse event. A suspected adverse reaction implies a lesser degree of certainty 
about causality than adverse reaction, which means any adverse event caused by a drug. 
7.1.3. Unexpected adverse reaction
An adverse event or suspected adverse reaction 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 or elsewhere in the current 
application. "Unexpected”, also refers to adverse events or suspected adverse reactions that 
are mentioned in the investigator brochure as occurring with a class of drugs or as anticipated 
from the pharmacological properties of the drug, but are not specifically mentioned as 
occurring with the particular drug under investigation. 
7.1.4. Serious 
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following: 
x
Death,


09-C-0189 
 
 35 
x
A life-threatening adverse drug experience 
x
Inpatient hospitalization or prolongation of existing hospitalization 
x
Persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
x
A congenital anomaly/birth defect. 
x
Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered a serious adverse drug experience when, 
based upon appropriate medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. 
7.1.5. Disability
A substantial disruption of a person’s ability to conduct normal life functions. 
7.1.6. Life-threatening adverse drug experience 
Any adverse event or suspected adverse reaction that places the patient or subject, in the view 
of the investigator or sponsor, at immediate risk of death from the reaction as it occurred, i.e., 
it does not include a reaction that had it occurred in a more severe form, might have caused 
death.
7.1.7. Protocol Deviation (NIH Definition)
A protocol deviation is any change, divergence, or departure from the study design or 
procedures of a research protocol that is under the investigator’s control and that has not been 
approved by the IRB.
7.1.8. Protocol Violation (NIH Definition)
Any change, divergence, or departure from the study procedures in an IRB-approved 
research protocol that has a major impact on the subject’s rights, safety, or well-being and/or 
the completeness, accuracy or reliability of the study data. 
7.1.9. Unanticipated Problem
Any incident, experience, or outcome that: 
x
Is unexpected in terms of nature, severity, or frequency in relation to  
(a) the research risks that are described in the IRB-approved research protocol and 
informed consent document; Investigator’s Brochure or other study documents, 
and
(b) the characteristics of the subject population being studied; AND 
x
Is related or possibly related to participation in the research; AND 
x
Places subjects or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or 
recognized.
7.2. Routine Data Reporting
7.2.1. Following randomization, all adverse events will be described in the source 
documents, reviewed by the designated research nurse, and captured in C3D.   


09-C-0189 
 
 36 
o
All chemotherapy dose reductions and the reason for the reduction will be 
captured in C3D 
o
During the follow up period (more than 30 days following the last treatment), 
only those events that are serious, unexpected, and related to the treatment 
will be captured in C3D.
7.2.2. Laboratory events will be captured as follows: 
o
During hospitalization for surgical resection, only the admission labs, first 
morning labs drawn after 4am, and labs that support the diagnosis of a 
reportable event will be uploaded into C3D. 
o
During systemic chemotherapy regimen, for laboratory values obtained at 
sites other than the NIH Clinical Center: only the following values (highest 
grade per cycle) will be captured in C3D: 

Hemoglobin, total white blood cell count, absolute neutrophil 
count, platelet count 

PTT, PT or INR 

Creatinine, ALT, AST, Bilirubin (total and direct),  

Any unexpected laboratory abnormality  grade 2 possibly, 
probably or definitely related to the research 
7.3. Exclusions to Routine Data Reporting:
The following Adverse Events will be captured only in the source documents and 
will not be reported in C3D 
7.3.1. For the duration of the study:
o
Laboratory values that do not support the diagnosis of a reportable event 
o
All grade 1 events 
7.3.2. During hospitalization for surgical resection 
o
Grade 2 events 
o
Grade 3 and 4 events which resolve during the first 72 hours following 
surgery 
7.3.3. Post operative recovery phase (following discharge) 
o
Grade 2 events 
7.3.4. During systemic chemotherapy administration 
o
Grade 1 and 2 events that are listed in the package insert of any of the agents 
o
Grade 3 events that are listed in the package insert of any of the agents and do 
NOT require hospitalization.  Events that initiate dose reduction will be 
captured as described in Section 7.1.1 
Note: Events that result in a hospitalization for convenience will not be reported. 
7.3.5. Concomitant medications:  


09-C-0189 
 
 37 
Only those medications that the patient is taking at baseline on a routine basis or 
medications that cause an AE will be captured in C3D.  {Thus onetime 
medications, PRN medications, and medications given to treat adverse events will 
not be captured in C3D.} 
7.4. NCI-IRB REPORTING
7.4.1. NCI-IRB Expedited Reporting of Adverse Events, Unanticipated Problems, and 
Deaths
The Protocol PI will report to the NCI-IRB: 
x
All unexpected serious adverse events that are possibly, probably, or definitely 
related to the research  
x
All deaths, except deaths due to progressive disease
x
All Protocol Violations or Deviations 
x
All Unanticipated Problems 
Reports must be received by the NCI-IRB within 7 working days of PI awareness via 
iRIS.
7.4.2. NCI-IRB Requirements for PI Reporting of Adverse Events at Continuing Review
The protocol PI will report to the NCI-IRB:  
x
All Grade 2 unexpected events that are possibly, probably or definitely related 
to the research;
x
All Grade 3 and 4 events that are possibly, probably or definitely related to the 
research;  
x
All Grade 5 events regardless of attribution;
x
All Serious Events regardless of attribution.
NOTE: Grade 1 events are not required to be reported 
8. Pharmaceutical Information:
8.1. Oxaliplatin 
8.1.1. Source:
Oxaliplatin is commercially available (manufacturer: Sanofi-Winthrop, France) and will 
be purchased from commercial sources by the NIH Clinical Center Pharmacy 
Department. 
8.1.2. Toxicities:
Predominant dose-limiting toxicity: sensory peripheral neuropathy.  Fifty-six percent of 
patients with this combined therapy experienced an acute, reversible primarily peripheral 
sensory neuropathy that is of early onset, occurring within hours or one or two days of 
dosing, that resolves within 14 days, and that frequently recurs with further dosing.  The 
symptoms may be precipitated or exacerbated by exposure to cold temperature or cold 
objects and they usually present as transient paresthesia, dysesthesia and hypoesthesia in 
the hands, feet, perioral area or throat. Jaw spasm, abnormal tongue sensation, dysarthria, 
eye pain, and a feeling of chest pressure have also been observed.  An acute syndrome of 
pharyngolaryngeal dysesthesia seen in 1-2 % of patients is characterized by subjective 
sensations of dysphagia or dyspnea, with laryngospasm or bronchospasm.  In 48% of 


09-C-0189 
 
 38 
patients receiving this combination, a persistent (> 14 days), primarily peripheral, sensory 
neuropathy that is usually characterized by paresthesias, dysethesias, hypoesthesias, but 
may also include deficits in proprioception that can interfere with daily activities (e.g., 
writing, buttoning, swallowing, and difficulty walking from impaired proprioception) has 
occurred.  Oxaliplatin has been associated with pulmonary fibrosis (0.7% of study 
patients), which may be fatal.  If patients experience unexplained respiratory symptoms 
such as non-productive cough, dyspnea, crackles, or radiological pulmonary infiltrates, 
the agent should be discontinued until further pulmonary investigation excludes 
pulmonary fibrosis or interstitial lung disease.  Other effects: nausea, vomiting, diarrhea, 
mucositis, transaminase elevations, and alopecia.  Myelosuppression is minimal with the 
agent alone but may be significant when given in combination with 5-FU/LV; severe 
nephrotoxicity not reported.  Extravasation of oxaliplatin may result in local pain and 
inflammation that may be severe and lead to complications, including necrosis.  Injection 
site reaction, including redness, swelling and pain have been reported. 
8.1.3. Formulation and Preparation: 
Oxaliplatin is supplied in clear, glass, single-use vials with gray elastomeric stoppers and 
aluminum flip-off seals containing 50 mg or 100 mg as a sterile, preservative-free 
lyophilized powder for reconstitution, containing lactose monohydrate as an inactive 
ingredient (450mg or 900 mg respectively).  For IV administration, the appropriate dose 
is reconstituted in a parenteral solution of 250 mL of 5% Dextrose Injection, USP (D5W). 
For CHPP administration, Oxaliplatin 460 mg/m2 is diluted in 2.0 L/m2 of D5W and 
administered via the perfusion circuit.  Reconstitution of final dilution must never be 
performed with a sodium chloride solution or other chloride-containing solutions. 
8.1.4. Stability/Storage:
Oxaliplatin is stable when stored under normal lighting conditions at room temperature of 
25(C (77(F).After reconstitution in the original vial, the solution may be stored up to 24 
hours under refrigeration (2-8(C (36-46(F).  After final dilution with 5% Dextrose 
Injection, USP, the shelf life is 6 hours at room temperature [20-25(C (68-77(F)] or up to 
24 hour under refrigeration [2-8(C (26-46(F)].  Oxaliplatin is not light sensitive. 
8.1.5. Administration:  
Oxaliplatin will be administered in a 250 mL solution of 5% Dextrose Injection, USP 
(D5W) as a 2 hour infusion on day one of each cycle concurrently with leucovorin in 
different IV lines. Oxaliplatin is incompatible in solution with alkaline medications or 
media and must not be mixed with these or administered simultaneously through one 
infusion line.  The infusion line should be flushed with D5W prior to administration of 
any concomitant medication. 
8.2. Leucovorin Calcium (Injection)
8.2.1. Source:
Leucovorin calcium injection will be purchased from commercial sources by the NIH 
Clinical Center Pharmacy Department. 


09-C-0189 
 
 39 
8.2.2. Toxicity:
Allergic sensitization has been reported following both oral and parenteral 
administrations of folinic acid.   
8.2.3. Formulation and Storage: 
Leucovorin calcium is supplied as 350 mg/vial dry powder and will be reconstituted 
with sterile water for injection, USP, to a concentration of 20mg/ml.  Intact vials of 
leucovorin need to be stored at controlled room temperature (25 degrees C) and 
protected room light. 
8.2.4. Stability:
Leucovorin has been administered extensively with FUDR and dexamethasone as a 2 
week intra-arterial infusion in patients with colorectal cancer and loses less than 10% 
of its activity in solution with these agents at more than 60 days of incubation. 
8.2.5. Administration Procedures: 
Leucovorin will also be administered on day 1 of each cycle at a dose of 200 mg/m2
intravenously over 2 hours concomitant with oxaliplatin.  Doses will be based on actual 
body weight if patient’s weight is within 20% of the ideal body weight.  If the patient’s 
weight is 20% above or below the ideal body weight, then ideal body weight will be 
used to calculate systemic chemotherapy doses.  Leucovorin will be diluted in 5% 
Dextrose Injection, USP (D5W). 
8.3. 5-Fluorouracil
8.3.1. Source:
It will be purchased commercially by the NIH Clinical Center Pharmacy Department. 
8.3.2. Toxicities:
The most common adverse reactions include stomatitis, esophagopharyngitis, diarrhea, 
anorexia, nausea, emesis, dermatitis, and alopecia. Hand-foot syndrome (palmar-plantar 
erythrodysesthesia) has been observed with 5-FU administration. Bone marrow 
suppression may occur at high doses with the lowest counts expected between the 9th and 
14th day of treatment.  Leukopenia is the most common hematologic toxicity associated 
with fluorouracil (5-FU) with the nadir typically between 9 and 14 days after treatment. 
The white blood cell count usually returns to normal after stopping treatment. Ischemic 
chest pain and myocardial ischemia or signs of electrocardiogram changes may occur 
with fluorouracil administration.  Onset of chest pain in many cases occurs within hours 
of receiving a second or third dose but may be associated with the first dose. Anginal 
attacks often recur upon rechallenge, but may or may not be prevented with vasodilators 
such as nitrates or calcium channel blockers. Death has occurred secondary to 
cardiogenic shock.  Most commonly, these effects occur when the drug is administered as 
a continuous infusion and within several hours from the start of the infusion.  Patients 
with pre-existing coronary artery disease (CAD) appear to be at greater risk; however, 
most reported cases are in those with no previous history of CAD. Neurological effects 
reported by the manufacturer include nystagmus, headache, disorientation and euphoria. 
Of 25 patients receiving low-dose leucovorin (20 mg/m2) and fluorouracil (425 to 600 
mg/m2), 15 (65%) developed hypocalcemia, and two each had tetany or hiccups.  


09-C-0189 
 
 40 
Calcium levels should be monitored in patients receiving this regimen, and calcium 
supplementation should be provided if calcium levels are low. The manufacturer reports 
that visual changes and photophobia have occurred with 5-fluorouracil use.
8.3.3. Formulation and Preparation:
5-FU (Fluorouracil) is supplied as a sterile, nonpyrogenic injectable solution for 
administration.  Each 10-cc contains 500 mg in a colorless to faint yellow aqueous 
solution.  The pH is adjusted to 9.2 with sodium hydroxide. 
8.3.4. Stability/Storage:
Fluorouracil solutions should be stored at room temperature and protected from light.  
Solutions may discolor slightly but potency and safety are not adversely affected.  Any 
precipitate which forms may be resolubilized by heating and agitation.  The stability of 
aqueous fluorouracil 50 mg/mL was studied in portable infusion pumps under simulated 
infusion conditions. The drug was found to be stable for 7 days at 37 °C.  Fluorouracil 
solution maintained 98% to 100% potency over 48 hours after dilution and storage in 
syringes or ethylene vinyl acetate infusion-pump reservoirs. 
8.3.5. Administration:   
Intravenous administration (Intra-operative)
Each 10 ml ampoule contains 500 mg of fluorouracil, and the appropriate amount is 
diluted in a parenteral solution of 5% Dextrose Injection, USP (D5W).  5-FU will be 
administered on days 1 and 2 of each cycle of systemic chemotherapy at a dose of 3200 
mg/m2 via continuous intravenous infusion over 48 hours. Doses will be based on actual 
body weight if patient’s weight is within 20% of the ideal body weight.  If the patient’s 
weight is 20% above or below the ideal body weight, then ideal body weight will be 
used to calculate systemic chemotherapy doses. See Section 3.2.2 for the calculation for 
ideal body weight. 
8.4. Irinotecan
8.4.1. Source:
Irinotecan is commercially available and will be purchased by the CC Pharmacy 
Department. 
8.4.2. Adverse effects:
The most clinically significant adverse events for patients receiving irinotecan-based 
therapy were diarrhea, nausea, vomiting, neutropenia, increased bilirubin, interstitial lung 
disease, and alopecia.  Irinotecan can induce both early and late forms of diarrhea that 
appear to be mediated by different mechanisms. Both forms of diarrhea may be severe. 
Early diarrhea (occurring during or shortly after infusion of irinotecan) may be 
accompanied by cholinergic symptoms of rhinitis, increased salivation, miosis, 
lacrimination, diaphoresis, flushing, and intestinal hyperperistalsis that can cause 
abdominal cramping. Early diarrhea and other cholinergic symptoms may be prevented or 
ameliorated by atropine late diarrhea (generally occurring more than 24 hours after 
administration of irinotecan) can be life threatening since it may be prolonged and may 
lead to dehydration, electrolyte imbalance, or sepsis. Late diarrhea should be treated 


09-C-0189 
 
 41 
promptly with loperamide. Patients with diarrhea should be carefully monitored and 
given fluid, and electrolyte replacement if they become dehydrated, or antibiotic therapy 
if they develop ileus, fever, or severe neutropenia. 
8.4.3. Formulation and preparation:
Irinotecan is supplied as 20 mg/mL solution (on the basis of the trihydrate salt); 45 mg 
sorbitol; and 0.9 mg lactic acid in single-dose amber 2mL (40 mg) and 5mL (100 mg) 
vials.  When necessary, pH has been adjusted to 3.5 (range, 3.0 to 3.8) with sodium 
hydroxide or hydrochloric acid. Solutions should be diluted in 5% Dextrose Injection, 
USP, (preferred) or 0.9% Sodium Chloride Injection, USP, to a final concentration range 
of 0.12 to 2.8 mg/mL using 100 to  500 mL of 5% Dextrose Injection, USP. 
8.4.4. Stability/Storage:
Store at controlled room temperature 15º to 30ºC (59º to 86ºF). Protect from light. It is 
recommended that the vial (and backing/plastic blister) should remain in the carton until 
the time of use. Admixtures are physically and chemically stable for up to 24 hours at 
room temperature (approximately 25ºC) and in ambient fluorescent lighting. Solutions 
diluted in 5% Dextrose Injection, USP, and stored at refrigerated temperatures 
(approximately 2º to 8ºC), and protected from light are physically and chemically stable 
for 48 hours. Refrigeration of admixtures using 0.9% Sodium Chloride Injection, USP, is 
not recommended due to a low and sporadic incidence of visible particulates. Freezing 
irinotecan stock solutions and irinotecan admixtures may result in precipitation of the 
drug and should be avoided. 
8.4.5. Administration:  
Doses will be diluted in 100 to 250 mL of 5% Dextrose Injection, USP or 0.9% Sodium 
Chloride Injection, USP and infused over 90 minutes. 


09-C-0189 
 
 42 
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     from gastric cancer.  Japanese Journal of Lung Cancer. 2007;47(4): 323-6. 
     57.      Konno H, Baba M, Nakamura S, Baba S.  A long surviving case of gastric cancer with
     metachronous liver and lung metastases. American Journal of Gastroenterology.  1995;    
     90(12): 2267-8. 
     58.      Tanaka T, Kaneda Y, Fujita N, Ueda K, Sakano H, Saeki K, Matsuoka T, Sudoh M,
     Hayashi M., Zempo N, Esato K.  A case of simultaneous resection of primary lung cancer and  
     pulmonary metastasis from gastric cancer. Journal of the Japanese Association for Chest  
     Surgery. 2000; 823-26. 
     59.       Pyrhonen S, Kuitunen T, Nyandoto P et al.     Randomised comparison of fluorouracil,  
     epidoxorubicin and methotrexate (FEMTX) plus supportive care with supportive care alone in  
     patients with non-resectable gastric cancer.  Br J Cancer. 1995; 71(3): 587-91. 
     60.       Ajani JA.  Evolving chemotherapy for advanced gastric cancer.  The Oncologist.     
     2005; 10(3): 49-58. 
     61.       Ajani JA, Moiseyenko VM, Tjulandin S et al. Clinical benefit with docetaxel plus
     fluorouracil and cisplatin compared with cisplatin and fluorouracil in a phase III trial of  
     advanced gastric or gastroesophageal cancer adenocarcinoma: the V-325 Study Group.  J Clin    
     Oncol. 2007; 25(22): 3205-9. 
     62.      Futatsuki K, Wakui A, Nakao I Late phase II study of irinotecan hydrochloride (CPT-
     11) in advanced gastric cancer. CPT-11 Gastrointestinal Cancer Study Group.  Gan To      
     Kagaku Ryoho. 1994; 21(7):1033-8. 
     63.     Bleiberg H.  CPT-11 in gastrointestinal cancer.  Eur J Cancer. 1999; 35(3):371-9. 
     64.     Yilmaz U, Oztop I, Alacacioglu A et al.  Irinotecan combined with infusional 5-      
      fluorouracil and high-dose leucovorin for the treatment of advanced gastric carcinoma as the  
      first-line chemotherapy.  Chemotherapy. 2006;52(5):264-70.  
     65.      Bouché O, Raoul JL, Bonnetain F et al. Randomized multicenter phase II trial of a    
      biweekly regimen of fluorouracil and leucovorin (LV5FU2), LV5FU2 plus cisplatin, or   
      LV5FU2 plus irinotecan in patients with previously untreated metastatic gastric cancer: a  
      Federation Francophone de Cancerologie Digestive Group Study--FFCD 9803.  : J Clin    
      Oncol. 2004;22(21):4319-28.   


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     66.      Pozzo C, Barone C, Szanto J et al. Irinotecan in combination with 5-fluorouracil and           
     folinic acid or with cisplatin in patients with advanced gastric or esophageal-gastric junction     
     adenocarcinoma: results of a randomized phase II study.  Ann Oncol. 2004;15(12):1773-81.    
     67.      Kim ST, Kang WK, Kang JH, et al.   Salvage chemotherapy with irinotecan, 5-   
     fluorouracil and leucovorin for taxane- and cisplatin-refractory, metastatic gastric cancer.  Br     
     J Cancer. 2005; 92(10):1850-4 
     68.      Louvet C, André T, Tigaud JM, et al.  Phase II study of oxaliplatin, fluorouracil, and
     folinic acid in locally advanced or metastatic gastric cancer patients.  J Clin Oncol.  
     2002;20(23):4543-8. 
     69.     Ychou M, Conroy T, Seitz JF, et al.  An open phase I study assessing the feasibility of
     the triple combination: oxaliplatin plus irinotecan plus leucovorin/ 5-fluorouracil every 2          
     weeks in patients with advanced solid tumors. Ann Oncol. 2003;14(3):481-9. 
     70.     Guichard S, Arnould S, Hennebelle I, et al. Combination of oxaliplatin and irinotecan  
     on human colon cancer cell lines: activity in vitro and in vivo.  Anticancer Drugs. 2001;  
     12(9):741-51. 
     71.     Masi G, Allegrini G, Cupini S, et. al. First-line treatment of metastatic colorectal    
     cancer with irinotecan, oxaliplatin and 5-fluorouracil/leucovorin (FOLFOXIRI): results of a
     phase II study with a simplified biweekly schedule.   Ann Oncol. 2004;15(12):1766-72. 
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      modulated fluorouracil in advanced pancreatic cancer--a Groupe Tumeurs Digestives of the    
      Federation Nationale des Centres de Lutte Contre le Cancer study .  J Clin Oncol. 2005;  
      23(6):1228-36. 
      73.     Lee J, Kang WK, Kwon JM et al.  Phase II trial of irinotecan plus oxaliplatin and 5-   
      fluorouracil/leucovorin in patients with untreated metastatic gastric adenocarcinoma.  Ann      
      Oncol. 2007;18(1):88-92.
      74.
Cao W, Yang W, Lou G, et. al.  Phase II trial of infusional fluorouracil, leucovorin,  
       oxaliplatin, and irinotecan (FOLFOXIRI) as first-line treatment for advanced gastric cancer.     
       Anticancer Drugs. 2009;20(4):287-93. 
      75.    Chevy WD, Wong BCY, et al.  American College of Gastroenterology Guideline  
      on the Management of Helicobacter pylori Infection.  2007; Am J Gastroenterol.; 102(8): 
      1808-1825. 
76.    Cunningham D, Rao D, Starling N, et al.  Randomised multicenter phase III study  
       comparing capecitabine with fluorouracil and oxaliplatin with cisplatin in patients    
       with advanced oesophagogastric (OG) cancer: The REAL-2 trial. J Clin Oncol    
       24:182s, 2006 
77.    Masi G, Loupakis F, Pollina L, et al. Long-term outcome of initially unresectable    
       metastatic colorectal cancer patients treated with 5-fluorouracil/leucovorin,      
 oxaliplatin, and irinotecan (FOLFOXIRI) followed by radical surgery of       
 metastases.  Ann Surg. 2009 Mar;249(3):420-5.  
       78.    Kawaramachi, Kamigyo-ku, Kyoto. Japanese Classification of Gastric Carcinoma 
       Gastric Cancer (1998) 1: 10–24 
       79.  Piantadosi S. Clinical Trials: A Methodologic  Perspective, New York: John Wiley and              
Sons, 1997, pp. 230-269 
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09-C-0189 
 
 47 
      81.  Reza Kianmanesh, MD, PhD, Stefano Scaringi, MD,Jean-Marc Sabate, MD, PhD, et.al., 
Iterative Cytoreductive Surgery Associated With Hyperthermic Intraperitoneal 
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Without Liver Metastases.  Ann Surg. 2007 April; 245(4): 597–603. 


09-C-0189 
 
 48 
10. Figures, Tables and Appendices
Table 1: Long-term survival for patients who underwent liver resection for metastatic gastric adenocarcinoma 
Authors
Country
Year
Number
of
patients
Median
survival
in
months
Mean
survival
in
months
1year
survival
in%
3year
survival
in%
5year
survival
in%
Numberof
patients
aliveat5
years
Numberof
treatment
related
deaths
Morise et. al.20
Japan  
2008 
18 
13 
- 
56 
27 
27 
3+ 
0 
Thelen et. al. 21
Germany  
2008 
24 
- 
- 
53 
22 
15 
2 
1 
Cheon et. al. 22
S. Korea  
2008 
22 
17 
- 
77 
30 
23 
3 
1 
Ueda et al.*23
Japan  
2008 
15 
- 
- 
80 
60 
60 
3 
0 
Sakamoto et.al26
Japan  
2007 
37 
31 
- 
- 
- 
11 
2 
0 
Koga et. Al24
Japan  
2007 
42 
34 
- 
76 
48 
42 
8 
2 
Roh et al.25
S. Korea  
2005 
11 
19 
- 
73 
38 
38 
1 
0 
Shirabe et al.27
Japan  
2003 
36 
 
- 
64 
26 
26 
4 
0 
Okano et al.28
Japan  
2002 
19 
21 
- 
77 
34 
34 
3 
0 
Saiura et al.29
Japan  
2002 
10 
25 
27 
50 
30 
20 
2 
3 
Zacherl et al.30
Austria  
2002 
15 
9 
16 
36 
29 
- 
0 
1 
Ambiru et al.31
Japan  
2001 
40 
12 
- 
- 
- 
18 
6 
0 
Imamura et al.32
Japan  
2001 
17 
- 
- 
47 
22 
0 
0 
0 
Fujii et al.33
Japan  
2001 
10 
16 
- 
60 
20 
10 
1 
1 
Elias et al.34
France  
1998 
11 
- 
- 
90 
35 
- 
4 
- 
Ochai et al.35
Japan  
1994 
21 
- 
- 
- 
- 
- 
4 
0 
Bines et al.36
USA  
1993 
10 
- 
- 
45 
  
30 
2 
3 
Total 
 
- 
358 
- 
- 
 
- 
- 
48 
12 
* 3 patients received microwave ablation therapy 







+ Alive at 4 years at time of follow up 









09-C-0189 
 
 49 
Table 2: Profile of Long Term Survivors (> 5 years)
            Study                   Age          Sex          Histology                   T            N             # Mets       Synch            Surgery                                      Survival 
        Koga et. al.         1. 
75 
F 
Poorly 
1-2 
1 
1 
Y 
Lobectomy 
Alive at 85 months 
                         2. 
56 
M 
Poorly 
1-2 
1 
1 
N 
Wedge 
Alive at 84 months 
                         3. 
65 
M 
Well 
1-2 
0 
1 
N 
Lobectomy 
Alive at 86 months 
                         4. 
61 
M 
Mod 
1-2 
3 
1 
Y 
Wedge 
Alive at 77 months 
                         5. 
52 
M 
Well 
1-2 
2 
1 
Y 
Wedge 
Alive at 78 months 
                         6. 
52 
F 
- 
1-2 
1 
1 
Y 
Wedge 
Alive at 65 months 
                         7. 
67 
F 
Mod 
1-2 
1 
1 
N 
Wedge 
Alive at 61 months 
                         8. 
61 
F 
Mod 
3 
1 
1 
Y 
Lobectomy 
Died at 71 months 
             Ueda et. al.        1. 
54 
M 
- 
2 
0 
1 
Y 
R lobectomy 
Alive at 136 months 
2. 
58 
M 
- 
2 
1 
1 
Y 
Wedge 
Alive at 107 months 
3. 
74 
F 
- 
3 
2 
1 
Y 
L lobectomy 
Alive at 71 months 
           Roh et. al.           1. 
69 
F 
Mod 
1 
2 
1 
Y 
Wedge 
Alive at 102 months 
                
64 
M 
Well 
3 
2 
1 
N 
Segmentectomy 
Alive at 102 months 
           Shirabe et. al.     1. 
- 
- 
Mod-Well 
3 
1 
1 
Y 
- 
Alive at 63 months 
                    2. 
- 
- 
Mod-Well 
1 
1 
1 
N 
- 
Died at 75 months(lung ca) 
                                       3. 
- 
- 
Mod-Well 
3 
1 
1 
N 
- 
Alive at 84 months 
                                       4. 
- 
- 
Mod-Well 
1 
1 
1 
Y 
- 
Alive at 207 months 
             Saiura et al.      1. 
59 
M 
Mod 
3 
0 
3 
N 
- 
Alive at 67 months 
                                      2. 
60 
F 
Mod 
2 
0 
10 
Y 
- 
Alive at 68 months 
            Okano et. al.     1. 
61 
M 
Well 
2 
1 
1 
N 
Wedge 
Alive at 138 months 
                                    2. 
75 
F 
Well 
3 
2 
1 
N 
Segmentectomy 
Alive at 96 months 
                                    3. 
69 
M 
Well 
2 
0 
1 
N 
Wedge 
Alive at 81 months 
           Fuji et. al.         1. 
41 
M 
Poorly 
4 
1 
1 
Y 
Wedge 
Alive at 245 months 
            Ochiai et. al     1. 
55 
M 
Well 
2 
1 
1 
Y 
Segmentectomy 
Alive at 218 months 
                                     2. 
52 
F 
Well 
2 
1 
1 
N 
Limited Resection 
Died at 77 months 
                                     3. 
49 
M 
Well 
2 
0 
6 
Y 
Segmentectomy 
Alive at 86 months 
          Bines et. al.       1. 
51 
M 
Poorly 
- 
1 
1 
Y 
L Lobectomy 
Alive at 120 months 
2. 
60 
M 
Well 
- 
1 
1 
Y 
L Lobectomy 
Alive at 156 months 
3. 
70 
F 
Variable 
- 
- 
1 
N 
Trisegmentectomy 
Died at 74 months 


09-C-0189 
 
 50 
Table 3: Eight Reports of Adjuvant Treatment with Perioperative Intraperitoneal  
                Chemotherapy in Gastric Cancer 37


09-C-0189 
 
 51 
Table 4: Lung Resections for Gastric Cancer 
Year 
Author 
Patients 
Pathology 
Operation 
Follow up 
1975 
Siono Y 
1 
adenocarcinoma 
 
 
1984 
Mai M 
1 
adenocarcinoma 
Lobectomy 
 
1988 
Tomita M 
1 
adenocarcinoma 
Lobectomy 
Died 9 months after resection 
1989 
Raute M 
1 
adenocarcinoma 
 
 
1989 
Umehara Y 
2 
adenocarcinoma 
 
 
1995 
Konno, H 
1 
adenocarcinoma 
Lobectomy 
NED at 4 years 
1996 
Piltz, S 
1 
adenocarcinoma 
 
 
1996 
Urabe M 
2 
adenocarcinoma 
Lobectomy/Wedge 
resection 
1 patient died at 3y, 5mo, 1 patient alive at 3 years, 3 mo 
1998 
Kamiyoshihara, 
M 
3 
adenocarcinoma 
Lobectomy/Wedge 
resection 
Mean survival: 22 months, 67% 1 year survival 
1998 
Kanemitsu, Y 
4 
adenocarcinoma 
Lobectomy 
Mean survival 24.3 months 
1998 
Tsumatori G 
5 
adenocarcinoma 
 
1 survivor > 5 years 
2000 
Tanaka T 
1 
adenocarcinoma 
Lobectomy 
 
2001 
Kobayashi, O 
1 
adenocarcinoma 
 
 
2001 
Kobayashi, O 
1 
adenocarcinoma 
 
 
2002 
Inage, Y 
1 
leiomyosarcoma 
Lobectomy 
 
2002 
Tamura M 
4 
adenocarcinoma 
 
Mean survival: 13.8 months 
2002 
Inoue Y 
1 
adenocarcinoma 
Lobectomy, 
Wedge 
resection
Alive 15 years after gastrectomy (7 years after first 
resection)
2004 
Nakahashi, C 
1 
adenocarcinoma 
Lobectomy, 
Wedge 
resection 
Alive 7 years after initial gastric resection 
2006 
Tsuboshima, K 
1 
adenocarcinoma 
Sternal 
resection/Wedge 
resection 
NED at 8 months 
2006 
Takahiro, S 
2 
adenocarcinoma 
Lobectomy/Wedge 
resection
2007 
Sakaguchi, K 
7 
adenocarcinoma 
Lobectomy/Wedge 
resection 
5 year OS: 42.9% 
2007 
Mikami K 
2 
adenocarcinoma 
 
 
2008 
Nakayama H 
1 
adenocarcinoma 
Lobectomy, Lobectomy 
Died 65 months after first lung resection from CVA 
 
 
 
 
 
 
Total 
45 
 
 
 


09-C-0189 
 
 52 
Figure 1: Tumor Cell Entrapment Hypothesis 37


09-C-0189 
 
 53 
APPENDIX I
Partial peritonectomy for gastric cancer 


09-C-0189 
 
 54 
Appendix 2 
First-Line Regimens for Helicobacter pylori Eradication 
 
 
 
 
 
 
 
            Am J Gastroenterol. 2007;102(8):1808-1825.


09-C-0189 
 
 55 
Appendix 3 
Trial Schema 


09-C-0189 
 
 56 
 Appendix 4    Dose Modification FOLFOXIRI 
eventͲgrade
irinotecan
oxaliplatin
5FU
neutropenia**
grade1
maintaindoselevel
maintaindoselevel
maintaindoselevel
grade2
maintaindoselevel
maintaindoselevel
maintaindoselevel
grade3
maintaindoselevel
maintaindoselevel
maintaindoselevel
grade4!5days
p1doselevel
p 1doselevel
maintaindoselevel
febrileneutropeniagrade4
p1doselevel
p 1doselevel
maintaindoselevel
thrombocytopenia**
grade1
maintaindoselevel
maintaindoselevel
maintaindoselevel
grade2
maintaindoselevel
maintaindoselevel
maintaindoselevel
grade3
p1doselevel
p 1doselevel
maintaindoselevel
grade4
p1doselevel
p 1doselevel
maintaindoselevel
anemia
grade1
maintaindoselevel
maintaindoselevel
maintaindoselevel
grade2
maintaindoselevel
maintaindoselevel
maintaindoselevel
grade3
maintaindoselevel
maintaindoselevel
maintaindoselevel
grade4
maintaindoselevel
maintaindoselevel
maintaindoselevel
diarrhea**
2Ͳ3stools/day>baseline
maintaindoselevel
maintaindoselevel
maintaindoselevel
4Ͳ6stools/day>baseline
maintaindoselevel
maintaindoselevel
maintaindoselevel
7Ͳ9stools/day>baseline
p1doselevel
maintaindoselevel
p1doselevel
t10stools/day>baseline
p2doselevels
maintaindoselevel
p2doselevels
mucositis/stomatitis**
grade1
maintaindoselevel
maintaindoselevel
maintaindoselevel
grade2
maintaindoselevel
maintaindoselevel
maintaindoselevel
grade3
maintaindoselevel
maintaindoselevel
p1doselevel
grade4
maintaindoselevel
maintaindoselevel
p2doselevels
handfootsyndrome
grade3Ͳ4
maintaindoselevel
maintaindoselevel
discontinue
othernonͲhemetoxicities*&**
grade1
maintaindoselevel
maintaindoselevel
maintaindoselevel
grade2
maintaindoselevel
maintaindoselevel
maintaindoselevel
grade3
p1doselevel
p 1doselevel
p1doselevel
grade4
p2doselevels
p 2doselevels
p2doselevels
neuropathy
grade1:resolvesͲdoesnot
interferewithfunctioning
maintaindoselevel
maintaindoselevel
maintaindoselevel
grade2:interfereswith
functioningbutnotdailyactivities
anddoesnotresolve
maintaindoselevel
maintaindoselevel
maintaindoselevel
grade3:painorfunctional
impairmentthatinterfereswith
dailyactivities
maintaindoselevel
discontinue
maintaindoselevel
grade4:persistentimpairment
thatisdisablingorlifeͲ
threatening.
maintaindoselevel
discontinue
maintaindoselevel
*excludesalopecia,anorexia,asthenia,labtoxicities
**Thenextdoseshouldbedelayeduntil:WBC>3000,neutrophils>1000Ͳplatelets>100,000


09-C-0189 
 
 57 
Appendix 5  
Lymph Node Stations 78


09-C-0189 
 
 58 
Regional lymph nodes 
No. 1    
Right paracardial LN 
No. 2   
Left paracardial LN 
No. 3   
LN along the lesser curvature 
No. 4sa 
LN along the short gastric vessels 
No. 4sb  
LN along the left gastroepiploic vessels 
No. 4d  
LN along the right gastroepiploic vessels 
No. 5   
Suprapyloric LN 
No. 6  
Infrapyloric LN 
No. 7   
LN along the left gastric artery 
No. 8a  
LN along the common hepatic artery 
 
 
(Anterosuperior group) 
No. 8p  
LN along the common hepatic artery (Posterior 
 
 
group) 
No. 9   
LN around the celiac artery 
No. 10  
LN at the splenic hilum 
No. 11p 
 LN along the proximal splenic artery 
No. 11d 
 LN along the distal splenic artery 
No. 12a 
 LN in the hepatoduodenal ligament (along the 
 
 
hepatic artery) 
No. 12b  
LN in the hepatoduodenal ligament (along the 
 
 
bile duct) 
No. 12p  
LN in the hepatoduodenal ligament (behind the 
 
 
portal vein) 
No. 13   
LN on the posterior surface of the pancreatic head 
No. 14v 
LN  
along the superior mesenteric vein 
No. 14a  
LN along the superior mesenteric artery 
No. 15  
LN along the middle colic vessels 
No. 16a1  
LN in the aortic hiatus 
No. 16a2  
LN around the abdominal aorta (from the upper 
 
 
margin of the celiac trunk to the lower margin 
 
 
of the left renal vein) 
No. 16b1  
LN around the abdominal aorta (from the lower 
 
 
margin of the left renal vein to the upper margin 
 
 
of the inferior mesenteric artery) 
No. 16b2 
 LN around the abdominal aorta (from the upper 
 
 
margin of the inferior mesenteric artery to the 
 
 
aortic bifurcation) 
No. 17  
LN on the anterior surface of the pancreatic head 
No. 18  
LN along the inferior margin of the pancreas 
No. 19  
Infradiaphragmatic LN 
No. 20  
LN in the esophageal hiatus of the diaphragm 
No. 110  
Paraesophageal LN in the lower thorax 
No. 111  
Supradiaphragmatic LN 
No. 112  
Posterior mediastinal LN


09-C-0189 
 
 59 
Appendix 6
Health Related Quality of Life forms - English 
Appendix 6a 
Health Related Quality of life forms - Spanish 


09-C-0189 
 
 60 
Appendix 7 
Sample Fax Cover Sheet and Patient Diary 

ICF_001.pdf: 
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• Adult Patient or 
• Parent, for Minor Patient 
INSTITUTE: 
National Cancer Institute 
STUDY NUMBER: 
09-C-0189 
PRINCIPAL INVESTIGATOR: 
Udo Rudloff,  M.D., PhD 
STUDY TITLE:  
Prospective Randomized Trial Comparing Gastrectomy, Metastasectomy plus Systemic Therapy 
versus Systemic Therapy Alone: GYMSSA Trial 
 
 
Continuing Review Approved by the IRB on 02/27/12 
Amendment Approved by the IRB on 05/21/12 (G) 
 
                                   Date Posted To Web:  06/06/12 
Standard 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent (1) 
 
 
INTRODUCTION 
We invite you to take part in a research study at the National Institutes of Health (NIH). 
First, we want you to know that: 
Taking part in NIH research is entirely voluntary.  
You may choose not to take part, or you may withdraw from the study at any time.  In either case, you will not 
lose any benefits to which you are otherwise entitled.  However, to receive care at the NIH, you must be taking 
part in a study or be under evaluation for study participation. 
You may receive no benefit from taking part.  The research may give us knowledge that may help people in the 
future. 
Second, some people have personal, religious or ethical beliefs that may limit the kinds of medical or research treatments 
they would want to receive (such as blood transfusions).  If you have such beliefs, please discuss them with your NIH 
doctors or research team before you agree to the study. 
Now we will describe this research study.  Before you decide to take part, please take as much time as you need to ask 
any questions and discuss this study with anyone at NIH, or with family, friends or your personal physician or other 
health professional.   
Why is this study being done?  
Gastric Cancer (stomach cancer) is a rare cancer. In most cases, by the time it has been diagnosed, it has spread to other 
organs in the body (metastasized) and the chance of a cure is very small.  The standard treatment for gastric cancer is a 
combination of chemotherapy drugs.  In this study, we want to see if removing all of the tumors first and then giving 
chemotherapy slows the growth of the cancer better than giving chemotherapy alone. In addition, we want to know how 
participants in each group feel during treatment; how well they are able to do their usual activities and how they rate 
their health. In order to gather this information, all participants will be asked to complete quality of life (QOL) 
questionnaires designed to show how people feel at the beginning of the study and about every 4 months during the 
study. 
 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 
09-C-0189 
CONTINUATION:  page  2  of  10  pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (10-84) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
 
 
Why are you being asked to take part in this study? 
 
You have cancer of the stomach which has spread to a few other organs in your body.  Based on your CT scans, we think 
that we could remove all of your tumors.  You have met all of the eligibility criteria for this study and so we feel that this 
procedure would be safe for you.   
 
How many people will take part in this Study?  
Approximately 136 people with gastric cancer will participate in this study. 
Description of Research Study 
This study is a randomized study; participants will be assigned to 2 different groups by chance (like flipping a coin).  Half 
of the participants will be assigned to have surgery first and then chemotherapy; the other half will be assigned to have 
chemotherapy alone.  This study has several stages as shown in the table below.  
 
 
Stage 
Timeframe 
Location 
Events 
Work up 
1-2 weeks 
Inpatient and out 
patient   
Scans, x-rays, labs, laparoscopy, QOL 
questionnaire, other tests as needed 
Randomization 
Following laparoscopy 
Surgery and recovery  
{for patients 
randomized to receive 
surgery + chemo} 
4-16 weeks 
In-patient, ICU 
and out-patient 
Number of days in the hospital and 
length of recovery will depend on the 
size and location of tumors 
Chemotherapy – will 
begin either within 2 
weeks of randomization 
{chemo only arm} or 6-
8 weeks following 
surgery {surgery + 
chemo group}. 
24 weeks 
NIH Clinical 
Center Day 
Hospital or home 
oncology clinic 
Physician visit, chemotherapy, labs 
every 2 weeks.  Scans every 8 weeks, 
QOL questionnaire every 16 weeks 
Follow up 
Every 3 months for 
2 years, then every 
6 months for 3 
years then yearly 
thereafter 
NIH Clinical 
Center as 
possible 
Includes physician visit, labs, scans 
and QOL questionnaires. 
 
Birth Control 
If you are a woman who is breast feeding or pregnant, you may not take part in the study because we don’t know how 
this medicine would affect your baby or your unborn child. If you are a woman who can become pregnant, or are the 
partner of a woman who can become pregnant, you will need to practice an effective form of birth control before starting 
study treatment, during study treatment, and for 6 months after you finish study treatment.  If you think that you or your 
partner is pregnant, you should tell your study doctor or nurse at once.   


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 
09-C-0189 
CONTINUATION:  page  3  of  10  pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (10-84) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
 
 
Effective forms of birth control include: 
• 
Abstinence  
• 
intrauterine device (IUD) 
• 
hormonal [birth control pills, injections, or implants] 
• 
tubal ligation 
• 
vasectomy 
What will happen if you take part in this research study?   
Before you begin the study 
Once we have determined that it is safe for you to participate in this study, you will have a laparoscopy.  This is a minor 
surgical procedure that uses a laparoscope, inserted through the abdominal wall, to examine the inside of the abdomen. 
A laparoscope is a thin, tube-like instrument with a light and a lens for viewing. It may also have a tool to remove tissue 
to be checked under a microscope for signs of disease.  The laparoscopy is to see how much tumor you have in your 
abdomen.  If you have too much disease, you will not be able to participate in the study.   
After we have the results of the laparoscopy, you will be randomized to either receive surgery followed by chemotherapy 
or chemotherapy alone. 
During the study 
Surgery 
If you are randomized to the surgery + chemotherapy group: 
In order to remove all of the tumors in your abdomen, you will need to have a major operation.  This will include 
removing the tumor as well as a large part of your stomach.  If you have tumors in your liver, the tumors and some of 
the surrounding normal tissue will be removed, if you have tumors on other organs they will be removed along with some 
of the normal surrounding tissue.  If you have tumors in your peritoneum (the thin film of tissue that covers all of your 
abdominal organs) this will be removed and you will undergo a procedure called Continuous Hyperthermic Peritoneal 
Perfusion (CHPP) while you are in the operating room (see below). 
After the operation you will be admitted to the Intensive Care Unit (ICU) where you will be monitored closely for 1-4 
days.  As with any major operation, you may have a breathing tube and be connected to a breathing machine for 1-2 
days following the operation.  You will have a tube in your stomach, a catheter (tube) in your bladder and several IVs 
during this period. As soon as you are able, you will be helped to get out of bed, to cough and take deep breaths and to 
walk.  Once your bowel function has returned to normal, you will be allowed to eat – this usually takes 4-7 days.   
When your condition is stable, you will be transferred to the regular patient care unit until you are ready to be discharged 
to home, usually 7-21 days following the operation.  Throughout your hospitalization, you will receive pain medications, 
IV fluids, antibiotics, and blood transfusions as necessary.    
CHPP (for patients with tumor in the peritoneum only) 
Near the end of the operation, after the tumors have been removed, two catheters (or thin tubes) will be put in your 
abdomen.  You will receive 3 chemotherapy drugs, 5-FU (also called 5-fluorouracil), leucovorin (LV), and oxaliplatin.  The 
5-FU and LV will be injected into your vein.  The oxaliplatin will be diluted in a heated solution and will be given to you 
through one catheter and drained out through another, bathing the inside of your abdomen with oxaliplatin.  This 
chemotherapy solution will be washed through your abdomen over 35 minutes at a temperature of about 108.6 degrees, 
which is 10 degrees above your normal body temperature.  After your abdomen has been bathed for 90 minutes, the 
chemotherapy will be rinsed out and the catheters will be removed.  During this procedure we will carefully monitor your 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 
09-C-0189 
CONTINUATION:  page  4  of  10  pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (10-84) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
 
 
temperature. If your body temperature goes up during the procedure, we will use cooling blankets and ice packs to keep 
your body temperature normal. 
If you have small tumors in your lung which can be removed, you will have surgery to remove the tumors after you 
recover from the abdominal surgery.  Your physician and the Thoracic surgeon will explain the surgery to you and you will 
be given a separate consent to sign.  After the operation to remove the tumors in your lung, you will be admitted to the 
ICU and then transferred to the regular patient care unit just as described above.  You will be hospitalized for about 1-3 
weeks depending on the location of your tumors.  
Chemotherapy 
If you are randomized to the chemotherapy group, you will begin treatment within 2 weeks following the laparoscopy.  If 
you are randomized to the surgery group, you will receive chemotherapy about 6-16 weeks following the operation(s).  
The drugs are given in your vein over 2 days every 2 weeks (one cycle) for 12 cycles (about 6 months).  You may receive 
the chemotherapy in the day hospital here at the NIH Clinical Center or at home with your referring oncologist. While you 
are receiving the drugs, you will need to have your blood drawn about once a week (more if you are having certain side 
effects), and you will need to see your doctor about every 2 weeks, right before the chemotherapy drugs are given, and 
you will have scans about every 8 weeks while you are on the chemotherapy. You will also be asked to keep a diary of all 
of the side effects you may have.    
You will receive 4 chemotherapy drugs, 5-Fluorouracil (5-FU), leucovorin (LV), oxaliplatin, and irinotecan.  These drugs 
are commonly given together for patients with colon cancer who have metastases in the liver and peritoneum and they 
have been effective in shrinking the tumors. The main side effects of these drugs when given together include, diarrhea, 
which can be severe, ulceration of the mouth, low blood counts, sensitivity to cold in the hands, feet and mouth, allergic 
reaction and fatigue. Your oncologist and chemotherapy nurse will review all of the side effects with you and discuss 
additional medications you may receive to help prevent or control the side effects.  It is also possible that you may lose 
your fertility following this treatment. If your side effects are severe or your tumors grow while you are taking the 
chemotherapy, the drugs will be stopped and your physician will discuss additional treatment options with you.  
Additional side effects are listed in the table in the Risks or Discomforts section. 
Follow up  
Once you have completed surgery and/or chemotherapy you will return to the NIH Clinical Center for follow up about 
every 3 months for 2 years, then every 6 months for 3 years and yearly thereafter.  If you are not able to return to the 
NIH Clinical Center, you will be contacted by phone.  
Health Related Quality of Life Forms (HRQOL) 
At several points during this study, we will ask you to complete 2 health related quality of life questionnaires.  This will 
take about 15 minutes and we will ask that you complete the questionnaires by yourself.  We will ask you to do this 
before you have your laparoscopy and then every 16 weeks for the first 2 years, then every 6 months for the next three 
years and yearly thereafter.  You can decide not to complete the questionnaires at any point and this will not affect your 
treatment.  
What other choices do I have if I do not take part in this study?  
 
Instead of being in this study, you have these options: 
• 
Getting chemotherapy or surgery for your cancer without being in a study 
• 
Taking part in another experimental study 
• 
Getting comfort care, also called palliative care.  This type of care helps reduce pain, tiredness, appetite problems 
and other problems caused by the cancer.  It does not treat the cancer directly.  Instead, it tries to improve how 
you feel.  Comfort care tries to keep you as active and comfortable as possible. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 
09-C-0189 
CONTINUATION:  page  5  of  10  pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (10-84) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
 
 
Please talk to your doctor about these and other options. 
What side effects or risks can I expect from being in this study?  
As described above, the main side effects of the chemotherapy include, diarrhea, which can be severe, ulceration of the 
mouth, low blood counts, sensitivity to cold in the hands, feet and mouth, allergic reaction, fatigue and loss of fertility. 
These risks are listed in the tables below.  
The operation to remove the gastric tumor and any other tumors throughout your abdomen is likely to be quite extensive 
and may incorporate CHPP as well. The risks from this operation and general anesthesia include:  
Likely 
• 
Pain  
• 
Temporary slowing or stopping of bowel function, known as an ileus. This could take several days to resolve and 
may require that the tube in your nose that drains your stomach stay in place longer 
• 
Laboratory studies of the liver, particularly bilirubin may be elevated.  This may be due to handling or removing 
part of the liver during surgery or it may be as a result of one of the chemotherapy drugs.  This usually does not 
cause any symptoms and resolves in a few days.  
• 
This surgery may also cause changes in your bowel pattern, either constipation or diarrhea.  Fluid may develop in 
your abdomen, known as ascites. This may go away on its own, or may need to be drained if it becomes too 
uncomfortable. 
Less Likely 
• 
Leakage of bowel contents may occur from an area where the bowel was sewn together or from any area of your 
bowel due to the effects of the chemotherapy, the increased temperature during CHPP, or from the surgery itself.  
This may cause an infection in your abdomen that may be life threatening and may require an additional 
operation to repair the leak.  Rarely this will cause openings to form from the bowel through the skin or into the 
abdomen (fistulas) that may require you to stay in the hospital longer, may require antibiotics, or require a 
second operation to repair.    
• 
The chemotherapy in your abdomen may also cause irritation to structures surrounding the abdomen, particularly 
the lining of your lungs.  This irritation may result in a condition called “pleural effusion” which means that the 
lung lining is irritated.  This may cause pain and some fluid may collect between the lining and the lung.  The 
fluid usually resolves by itself, but on occasion it may need to be drained with a needle and syringe, if it is 
causing difficulty breathing.   
• 
Bleeding which might require transfusions or a second operation to correct 
• 
Blood clots that have the risk of moving to the lungs causing difficulty breathing 
• 
Infection in the abdomen, where the incision was made, or in the lungs (pneumonia).  All types of infections 
would be treated with antibiotics.   
 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 
09-C-0189 
CONTINUATION:  page  6  of  10  pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (10-84) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
 
 
Rare but serious: 
• 
Heart failure, lung failure, kidney failure, liver failure, blood clots in your extremities or lungs and stroke  This 
may require treatment in the ICU including need for a breathing machine, dialysis, and blood pressure 
medications. 
• 
Damage to the various organs of your body which may cause your death. 
 
Risks: Oxalipaltin + 5-FU/LV 
Likely – these may be mild to severe 
Less Likely – these may be mild to severe 
Rare but Serious 
• 
Tingling of the mouth, lips, hands 
and feet - Sensitivity to cold in the 
mouth, hands and feet 
• 
Nausea, vomiting, diarrhea,  loss 
of appetite, weight loss, 
constipation, abdominal pain 
• 
Ulceration of the mouth 
• 
Decrease in blood counts including 
white blood cells (which increase 
the risk of infection), red cells 
(which may cause fatigue and 
weakness) and platelets (which 
increase the risk of bleeding). 
• 
Tiredness, insomnia, muscle 
aches, dizziness 
• 
Changes in taste and smell 
• 
Cough, shortness of breath 
• 
Hair loss 
• 
Tumor lysis syndrome  (A change in 
certain chemicals in the blood, which 
may cause damage to organs, 
including the kidneys, heart, and liver.) 
• 
Flushing, runny nose, eye irritation, 
headache, fever 
• 
Rash – particularly on the hands 
and feet 
• 
Changes in lab values that cause no 
symptoms and may or may not require 
treatment 
• 
Hiccups  
• 
Mood changes 
• 
Low blood 
pressure 
• 
Blood clots 
• 
Severe allergic 
reaction 
• 
Death 
 
 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 
09-C-0189 
CONTINUATION:  page  7  of  10  pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (10-84) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
 
 
 
Risks: Irinotecan + 5-FU/LV 
Likely – these may be mild to severe 
Less Likely – these may be mild to severe 
Rare but Serious 
• 
Diarrhea, this can be mild to 
severe and can occur immediately 
following the drug or several days 
later 
• 
Runny nose, tearing eyes, 
abdominal cramping, increased 
salivation 
• 
Nausea, vomiting, constipation, 
loss of appetite, weight loss 
• 
Decrease in blood counts including 
white blood cells (which increase 
the risk of infection), red cells 
(which may cause fatigue and 
weakness) and platelets (which 
increase the risk of bleeding). 
• 
Tiredness, insomnia, fever, muscle 
aches, pain, dizziness 
• 
Cough, shortness of breath 
• 
Changes in taste and smell 
• 
Hair loss  
• 
Rash – particularly on the hands and 
feet 
• 
Changes in lab values that cause no 
symptoms and may or may not require 
treatment 
• 
Low blood 
pressure 
• 
Blood clots 
• 
Death 
 
 
Potential Benefits of Participation 
 
Are there benefits to taking part in this study? 
It is possible that we may be able to remove all of your tumors and that the chemotherapy will keep them from returning 
but we don’t know if this will happen.   
The aim of this study is to see if undergoing surgery before chemotherapy will keep people cancer free longer than 
chemotherapy alone.  We don’t know if this is the case.  We hope that you will get personal medical benefit from taking 
part in this study, but we cannot be certain.  Because there is not much information about this treatment, we do not 
know if you will benefit from taking part in this study, although the knowledge gained from this study may help others in 
the future who have cancer.   
 
Research Subject’s Rights 
What are the costs of taking part in this study?  
If you choose to take part in the study, the following will apply, in keeping with the NIH policy: 
• 
You will receive study treatment at the NIH Clinical Center at no charge to you. This may 
include surgery, medicines, laboratory testing, x-rays or scans done at the Clinical Center, 
National Institutes of Health (NIH). 
• 
If you receive chemotherapy from your local oncologist, that treatment will be billed to your 
insurance company and you will be responsible for all co-payments and other charges not 
covered by your insurance company. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 
09-C-0189 
CONTINUATION:  page  8  of  10  pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (10-84) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
 
 
• 
Medicines that are not part of the study treatment and are not given at the Clinical Center will 
not be provided or paid for by the Clinical Center, NIH. 
• 
Once you have completed taking part in the study, medical care will no longer be provided by 
the Clinical Center, NIH. 
Stopping Therapy  
Your doctor may decide to stop your therapy for the following reasons: 
• 
if he/she believes that it is in your best interest 
• 
if your disease comes back during treatment 
• 
if you have side effects from the treatment that your doctor thinks are too severe 
• 
if new information shows that another treatment would be better for you 
 
In this case, you will be informed of the reason therapy is being stopped. 
 
You can stop taking part in the study at any time. However, if you decide to stop taking part in the study, we would like 
you to talk to the study doctor and your regular doctor first. 
 
Conflict of Interest 
 
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts of interest.  The 
following link contains details on this process http://ethics.od.nih.gov/procedures/COI-Protocol-Review-Guide.pdf.  
You may ask your research team for a copy of the Protocol Review Guide or for more information.  Members of the 
research team who do not work for NIH are expected to follow these guidelines but they do not need to report their 
personal finances to the NIH. 
 
Members of the research team working on this study may have up to $15,000 of stock in the companies that make 
products used in this study.  This is allowed under federal rules and is not a conflict of interest.  
 
 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• Adult Patient or 
• Parent, for Minor Patient 
STUDY NUMBER: 
09-C-0189 
CONTINUATION:  page  9  of  10  pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
(Continuation Sheet) 
• Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
OTHER PERTINENT INFORMATION 
1. Confidentiality. When results of an NIH research study are reported in medical journals or at scientific meetings, 
the people who take part are not named and identified.  In most cases, the NIH will not release any information 
about your research involvement without your written permission.  However, if you sign a release of information 
form, for example, for an insurance company, the NIH will give the insurance company information from your medical 
record.  This information might affect (either favorably or unfavorably) the willingness of the insurance company to 
sell you insurance. 
The Federal Privacy Act protects the confidentiality of your NIH medical records.  However, you should know that the 
Act allows release of some information from your medical record without your permission, for example, if it is 
required by the Food and Drug Administration (FDA), members of Congress, law enforcement officials, or authorized 
hospital accreditation organizations. 
2. Policy Regarding Research-Related Injuries.  The Clinical Center will provide short-term medical care for any 
injury resulting from your participation in research here.  In general, no long-term medical care or financial 
compensation for research-related injuries will be provided by the National Institutes of Health, the Clinical Center, or 
the Federal Government.  However, you have the right to pursue legal remedy if you believe that your injury justifies 
such action. 
3. Payments.  The amount of payment to research volunteers is guided by the National Institutes of Health policies.  In 
general, patients are not paid for taking part in research studies at the National Institutes of Health.  Reimbursement 
of travel and subsistence will be offered consistent with NIH guidelines. 
4. Problems or Questions.   If you have any problems or questions about this study, or about your rights as a 
research participant, or about any research-related injury, contact the Principal Investigator, Udo Rudloff, M.D., 
PhD, Building 10, Room 4-5950 Telephone:  301-496-3098.  
You may also call the Clinical Center Patient Representative at 301-496-2626. 
5. Consent Document.  Please keep a copy of this document in case you want to read it again.


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• Adult Patient or 
• Parent, for Minor Patient 
STUDY NUMBER: 
09-C-0189 
CONTINUATION:  page  10  of  10  pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
(Continuation Sheet) 
• Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
 
 
COMPLETE APPROPRIATE ITEM(S) BELOW: 
 
A. Adult Patient’s Consent 
B. Parent’s Permission for Minor Patient. 
I have read the explanation about this study and have been given the 
opportunity to discuss it and to ask questions.  I hereby consent to take 
part in this study. 
I have read the explanation about this study and have been given the 
opportunity to discuss it and to ask questions.  I hereby give permission 
for my child to take part in this study.   
(Attach NIH 2514-2, Minor’s Assent, if applicable.) 
 
  
 
 
  
 
Signature of Adult Patient/Legal Representative 
Date 
 
 
 
Print Name 
Signature of Parent(s)/Guardian 
Date 
 
 
 
Print Name 
C. Child’s Verbal Assent (If Applicable) 
The information in the above consent was described to my child and my child agrees to participate in the study. 
 
 
 
  
 
 
 
 
Signature of Parent(s)/Guardian 
Date 
 
Print Name 
THIS CONSENT DOCUMENT HAS BEEN APPROVED FOR USE  
FROM FEBRUARY 27, 2012 THROUGH FEBRUARY 26, 2013. 
 
 
 
  
 
 
  
 
Signature of Investigator 
Date 
 
 
 
Print Name 
Signature of Witness 
Date 
 
 
 
Print Name