Clinical trial NCT03092518
Conditions: Gastric Adenocarcinoma Esophagogastric Junction Gastric Cancer
Keywords: Surgical Resection Progression Free Survival Gastroesophageal junction (Siewert III) adenocarcinoma
Sponsor: National Cancer Institute (NCI)
Start date: 2017-06-05; Completion date: 2024-07-24
Enrollment: 27 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Background:

\- Gastric cancer is a common and serious cancer. Standard treatment is chemotherapy drugs. Researchers want to see if a new treatment helps. It is surgical removal of the cancer and heated chemotherapy delivered to the abdominal cavity called Hyperthermic intraperitoneal chemotherapy (HIPEC).

Objective:

\- To test if surgical removal of tumors plus heated intraperitoneal chemotherapy can improve survival in people with gastric cancers.

Eligibility:

\- People ages 18 and older with gastric cancer who can have most tumors surgically removed

Design:

* Participants will be screened with:
* Medical history
* Physical exam
* Blood, urine, and heart tests
* Scans
* Tissue sample from previous surgery
* Endoscopy with biopsy: A tube with a camera goes through the mouth and into the stomach. It and takes a sample of stomach tissue. Participants may get medicine to make them drowsy.
* Laparoscopy: Small cuts are made in the abdomen. A thin tube with a light and camera is inserted into the abdomen. Participants sleep through the procedure.

Participants will stay in the hospital. They will have:

* Surgery to remove as many tumors as possible.
* HIPEC for 60 minutes: Two thin tubes are put into the abdomen. Two chemotherapy drugs are given through one tube. They are drained out through another at a temperature a few degrees above normal body temperature. Another drug is given in a vein.
* Recovery for 7-21 days: Participants will have tubes in their stomach and bladder and intravenous (IVs) for a few days. They will get pain medicine, IV fluids, antibiotics, and blood transfusions as needed.
* Participants will have visits every few months for 3 years, then one a year. Visits include physical exam, blood tests, and scans. They also include dietary assessment and questions.

Detailed description:
Background:

* An estimated 24,590 cases of gastric adenocarcinoma are diagnosed annually in the United States (U.S.).
* The peritoneal surface is a site of metastasis found often at time of diagnosis and is a common (40%) site of recurrence.
* Laparoscopy with peritoneal lavage and cytopathologic analysis is a staging modality that can identify a subset of patients with microscopic peritoneal metastasis prior to consideration for definitive surgical therapy.
* Intraperitoneal chemotherapy has been employed in advanced gastric cancers and as an adjuvant with an associated improvement in survival in systematic reviews.

Objectives:

\- Determine the overall survival in patients with cytology-positive gastric cancer treated with Hyperthermic intraperitoneal chemotherapy (HIPEC) and gastrectomy.

Eligibility:

* Histologically confirmed adenocarcinoma of the stomach.
* Cytopathologic evidence of peritoneal carcinomatosis.
* Medically fit for systemic chemotherapy, HIPEC and gastrectomy.

Design:

\- Single arm, Phase II study of HIPEC and gastrectomy.

Arms: arm 1: Heated Intraperitoneal Chemotherapy (HIPEC) with gastrectomy
Interventions: intervention 1: Surgery intervention 2: Cisplatin intervention 3: Mitomycin C intervention 4: Sodium Thiosulfate intervention 5: Tumor Biopsy intervention 6: CT C/A/P intervention 7: PET-CT intervention 8: MRI intervention 9: EKG
Intervention descriptions: intervention 1: Heated Intraperitoneal Chemotherapy (HIPEC) with gastrectomy using cisplatin, mitomycin C and sodium thiosulfate intervention 2: Cisplatin (90 mg/m\^2) will be administered via circuit to the peritoneal cavity intervention 3: Mitomycin C 10 mg/m\^2 will be administered via circuit to the peritoneal cavity intervention 4: Sodium thiosulfate will be administered by continuous intravenous infusion starting immediately prior to the chemotherapy perfusion and continuing for a total of 12 hours. intervention 5: At screening, baseline (if not done at screening) and operation (as clinically indicated). intervention 6: At screening, baseline (if not done at screening), post op care, post-discharge visits/follow-up, semi-annual follow-up and annual follow-up. intervention 7: At screening, baseline (if not done at screening), post op care, post-discharge visits/follow-up, semi-annual follow-up and annual follow-up. intervention 8: If computed tomography (CT) contraindicated. intervention 9: At screening and baseline (if not done at screening).

Protocol documents:
Prot_SAP_000.pdf: 
1
Abbreviated Title: HIPEC for Gastric Cancer
Version Date: 12/28/2021
Abbreviated Title: HIPEC for Gastric Cancer
NIH Protocol: 17C0070 
Version Date: 12/28/2021
NCT Number: NCT03092518
Title: Phase II Trial of Heated Intraperitoneal Chemotherapy and Gastrectomy for Gastric 
Cancer with Positive Peritoneal Cytology
NCI Principal Investigator:
Jeremy L. Davis, MD 
Surgical Oncology Program (SOP), CCR, NCI, NIH 
Building 10, Room 4-3760
10 Center Drive
 
Bethesda, MD 20892
Phone: 240-858-3731
Email: jeremy.davis@nih.gov
Investigational Agents: None
Commercial Agents: Cisplatin, Mitomycin C, Sodium Thiosulfate


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Abbreviated Title: HIPEC for Gastric Cancer
Version Date: 12/28/2021
PRÉCIS 
Background:

An estimated 24,590 cases of gastric adenocarcinoma are diagnosed annually in the U.S.

The peritoneal surface is a site of metastasis found often at time of diagnosis and is a 
common (40%) site of recurrence.

Laparoscopy with peritoneal lavage and cytopathologic analysis is a staging modality that 
can identify a subset of patients with microscopic peritoneal metastasis prior to 
consideration for definitive surgical therapy.

Intraperitoneal chemotherapy has been employed in advanced gastric cancers and as an 
adjuvant with an associated improvement in survival in systematic reviews.
Objective:

Determine the overall survival in patients with cytology-positive gastric cancer treated with 
HIPEC and gastrectomy.
Eligibility:

Histologically confirmed adenocarcinoma of the stomach.

Cytopathologic evidence of peritoneal carcinomatosis.

Medically fit for systemic chemotherapy, HIPEC and gastrectomy.
Design:

Single arm, Phase II study of HIPEC and gastrectomy.


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Abbreviated Title: HIPEC for Gastric Cancer
Version Date: 12/28/2021
TABLE OF CONTENTS 
PRÉCIS...........................................................................................................................................2
TABLE OF CONTENTS ................................................................................................................3
STATEMENT OF COMPLIANCE ................................................................................................7
1
INTRODUCTION ...................................................................................................................7
1.1
Study Objectives ...............................................................................................................7
1.1.1
Primary Objective......................................................................................................7
1.1.2
Secondary Objectives ................................................................................................7
1.2
Background and Rationale................................................................................................7
1.2.1
Rationale for Palliative Gastrectomy and Regional Therapy in Gastric Cancer .......8
1.2.2
Drivers of Peritoneal Metastasis in Gastric Cancer.................................................10
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT .......................................................12
2.1
Eligibility Criteria ...........................................................................................................12
2.1.1
Inclusion Criteria .....................................................................................................12
2.1.2
Exclusion Criteria ....................................................................................................13
2.1.3
Recruitment Strategies.............................................................................................13
2.2
Screening Evaluation ......................................................................................................13
2.2.1
Screening Activities Performed Prior to Obtaining Informed Consent...................13
2.2.2
Screening Activities Performed After a Consent for Screening Has Been Signed .14
2.3
Participant Registration and Status Update Procedures..................................................14
2.3.1
Screen Failures.........................................................................................................15
2.3.2
Treatment Assignment Procedures..........................................................................15
2.4
Baseline Evaluation.........................................................................................................15
2.4.1
Within 8 Weeks Prior to Treatment with HIPEC ....................................................15
2.4.2
Within 4 Weeks Prior to Treatment with HIPEC ....................................................15
2.4.3
Pre-Operation Visit (Prior to Treatment with HIPEC)............................................16
3
STUDY IMPLEMENTATION .............................................................................................16
3.1
Study Design...................................................................................................................16
3.2
Drug Administration .......................................................................................................16
3.2.1
Cisplatin and Mitomycin .........................................................................................17
3.2.2
Sodium Thiosulfate..................................................................................................17
3.3
Study Calendar................................................................................................................18


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3.4
Surgical Guidelines.........................................................................................................22
3.4.1
Preoperative Patient Management ...........................................................................22
3.4.2
Patient Management in the Operating Room...........................................................22
3.4.3
Postoperative Care...................................................................................................23
3.4.4
Discharge (As Clinically Indicated) ........................................................................24
3.4.5
Post-Discharge/Follow-Up ......................................................................................24
3.4.6
Measurement of Health-Related Quality of Life for Research................................25
3.5
Cost and Compensation ..................................................................................................26
3.5.1
Costs ........................................................................................................................26
3.5.2
Compensation ..........................................................................................................26
3.5.3
Reimbursement........................................................................................................26
3.6
Criteria for Removal from Protocol Therapy and Off Study Criteria.............................26
3.6.1
Criteria for Removal from Protocol Therapy ..........................................................26
3.6.2
Off-Study Criteria....................................................................................................26
3.6.3
Lost to Follow-Up....................................................................................................27
4
CONCOMITANT MEDICATIONS/MEASURES...............................................................27
5
CORRELATIVE STUDIES ..................................................................................................27
5.1
Biospecimen Collection and Processing for Research....................................................27
6
DATA COLLECTION AND EVALUATION .....................................................................28
6.1
Data Collection ...............................................................................................................28
6.1.1
Routine Data Collection ..........................................................................................28
6.2
Data Sharing Plans..........................................................................................................29
6.2.1
Human Data Sharing Plan .......................................................................................29
6.2.2
Genomic Data Sharing Plan.....................................................................................30
6.3
Response Criteria ............................................................................................................30
6.3.1
Methods for Evaluation of Measurable Disease......................................................30
6.3.2
Progression-Free Survival .......................................................................................32
6.4
Toxicity Criteria..............................................................................................................32
7
NIH REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN.....32
7.1
Definitions.......................................................................................................................32
7.2
OHSRP Office of Compliance and Training/IRB Reporting..........................................32
7.2.1
Expedited Reporting ................................................................................................32


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7.2.2
IRB Requirements for PI Reporting at Continuing Review ....................................32
7.3
NCI Clinical Director Reporting.....................................................................................33
7.4
NIH Required Data and Safety Monitoring Plan............................................................33
7.4.1
Principal Investigator/Research Team.....................................................................33
8
STATISTICAL CONSIDERATIONS ..................................................................................33
9
COLLABORATIVE AGREEMENTS..................................................................................34
10
HUMAN SUBJECTS PROTECTIONS................................................................................34
10.1
Rationale For Subject Selection ..................................................................................34
10.2
Participation of Children .............................................................................................34
10.3
Participation of Subjects Unable to Give Consent ......................................................35
10.4
Evaluation of Benefits and Risks/Discomforts ...........................................................35
10.4.1
Risks ........................................................................................................................35
10.4.2
Potential Benefits.....................................................................................................36
10.5
Risks/Benefits Analysis...............................................................................................36
10.6
Consent Process and Documentation ..........................................................................37
10.6.1
Consent Process for Adults Who Lack Capacity to Consent to Research 
Participation...........................................................................................................................37
10.6.2
Request for Waiver of Consent for Screening Activities ........................................37
11
REGULATORY AND OPERATIONAL CONSIDERATIONS..........................................38
11.1
Study Discontinuation and Closure.............................................................................38
11.2
Quality Assurance and Quality Control ......................................................................38
11.3
Conflict of Interest Policy ...........................................................................................39
11.4
Confidentiality and Privacy.........................................................................................39
12
PHARMACEUTICAL INFORMATION .............................................................................40
12.1
Cisplatin.......................................................................................................................40
12.1.1
Source ......................................................................................................................40
12.1.2
Toxicity....................................................................................................................40
12.1.3
Formulation and Preparation ...................................................................................40
12.1.4
Stability and Storage................................................................................................40
12.1.5
Administration Procedures ......................................................................................41
12.1.6
Incompatibilities ......................................................................................................41
12.2
Mitomycin ...................................................................................................................41


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Abbreviated Title: HIPEC for Gastric Cancer
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12.2.1
Source ......................................................................................................................41
12.2.2
Toxicity....................................................................................................................41
12.2.3
Formulation and Preparation ...................................................................................41
12.2.4
Stability and Storage................................................................................................41
12.2.5
Administration Procedures ......................................................................................41
12.2.6
Incompatibilities ......................................................................................................41
12.3
Sodium Thiosulfate .....................................................................................................41
12.3.1
Source ......................................................................................................................41
12.3.2
Toxicity....................................................................................................................42
12.3.3
Formulation and Preparation ...................................................................................42
12.3.4
Stability and Storage................................................................................................42
12.3.5
Administration Procedures ......................................................................................42
12.3.6
Incompatibilities ......................................................................................................43
13
REFERENCES ......................................................................................................................44
14
APPENDICES .......................................................................................................................49
14.1
Appendix A: Performance Status Criteria...................................................................49
14.2
Appendix B: FACT-Ga (Version 4)............................................................................50
14.3
Appendix C: Carcinomatosis Extent Evaluation.........................................................53
14.4
Appendix D: General Specimen Collection Reference (Refer to Official Timepoints 
in Protocol 13C0176).................................................................................................................54
15
TABLES AND FIGURES.....................................................................................................55
15.1
Table 1: Systematic Review........................................................................................55
15.2
Table 2: Cytopathologic Analysis Definitions ............................................................58
15.3
Figure 1: Overall Survival of Patients with Positive Cytology Only Compared to 
Visible Metastatic Disease at Time of Laparoscopy .................................................................59
15.4
Figure 2: Random Effect Model Indicating Potential Survival Advantage of IP 
Chemo in Systematic Literature Review ...................................................................................60
15.5
Figure 3: OncoPrint Indicating Recurring Genomic Alterations in Multiple Gastric 
Adenocarcinoma Subtypes ........................................................................................................61


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Abbreviated Title: HIPEC for Gastric Cancer
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STATEMENT OF COMPLIANCE
The trial will be carried out in accordance with International Conference on Harmonisation Good 
Clinical Practice (ICH GCP) and the following: 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812) 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training.
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval. Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled. Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study. In addition, all changes to the consent form will be IRB-approved; an 
IRB determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form.
1
INTRODUCTION
1.1
STUDY OBJECTIVES
1.1.1
Primary Objective

Determine overall survival (OS) in patients with cytology-positive gastric cancer treated 
with HIPEC and gastrectomy.
1.1.2
Secondary Objectives

Determine intraperitoneal progression free survival (iPFS).

Determine distant (extra-peritoneal) disease free survival.

Describe the morbidity of this treatment strategy.
1.2
BACKGROUND AND RATIONALE
Gastric cancer was diagnosed in an estimated 24,590 people in the United States in 2015 and 
10,720 were estimated to die of the disease.1 Worldwide, there are nearly 1 million estimated new 
cases of gastric cancer per year with over 700,000 estimated deaths, making it the third most 
common cause of cancer-related death.2 An estimated 40% of patients will develop some form of 
peritoneal metastasis during the course of the disease.3,4 The 5-year overall survival for patients 
presenting with gastric adenocarcinoma in the U.S. is approximately 25–30%.5,6 Although the 
current treatment paradigm of surgical resection and systemic therapy aims to increase recurrence-
free and overall survival, peritoneal tumor dissemination remains a source of major morbidity and 
often a leading contributor to mortality.3 
The process of peritoneal dissemination begins early, as retrospective studies have shown that 
positive peritoneal cytology is present in 7% of patients at time of curative surgery, in the absence 
of macroscopic metastasis.7 Patients with positive peritoneal cytology (cyto+) experience cancer-
specific outcomes similar to those with gross metastatic disease (Figure 1).8-10 


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Abbreviated Title: HIPEC for Gastric Cancer
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Therefore, in addition to staging laparoscopy, peritoneal lavage with cytopathologic examination 
is designed to detect this subset of patients with occult metastatic disease and avoid non-curative 
gastric resection.7 Laparoscopic staging can prevent non-curative laparotomy in 23–31% of 
patients harboring metastasis not detected by radiography in patients with resectable gastric 
cancer.11,12 This is an important distinction between gastric cancer and other gastrointestinal 
malignancies because microscopic peritoneal (cyto+ M1) disease is an indication for palliative 
systemic chemotherapy. The median survival for patients with cyto+ M1 gastric cancer is 12 
months.13 It follows that, outside of a clinical trial, gastrectomy has not been advocated routinely 
for patients with positive peritoneal cytology, even as the only site of metastatic disease.
The primary risk factor associated with detection of occult peritoneal metastasis is advanced tumor 
stage. Detection rates rise with increasing pathologic T-stage, such that patients with T0-T2 gastric 
cancers have a low rate (2%) of positive cytology whereas T3-T4 tumors, or tumors with gross 
serosal invasion, have a 10-12% rate of positive cytology7,14.  Increased incidence of positive 
cytology has been associated also with preoperative TNM stage, such that clinical stage III tumors 
(AJCC 6th ed.) have an 11% incidence of positive peritoneal cytology7. Comparatively, two-thirds 
of patients with visible carcinomatosis will have positive peritoneal cytology. Most interesting is 
that metastases may be limited to the peritoneum in up to 73% of patients with peritoneal 
carcinomatosis.3,11,12
The natural history of patients with positive peritoneal cytology was studied by Mezhir and 
colleagues.13 The incidence of positive cytology was 23% (291 of 1241) in gastric cancer patients 
undergoing staging laparoscopy with peritoneal washings. Of those 291 patients, 32% (93 of 291) 
had positive cytology in the absence of gross metastatic disease. While the median disease-specific 
survival for the entire cohort was 1 year, a subset of patients who received systemic chemotherapy 
and then underwent repeat laparoscopy was analyzed. Patients who converted to negative cytology 
experienced significantly improved survival compared to those with persistently positive 
peritoneal cytology (2.5 vs 1.4 years, p=0.0003). This finding resembles that of neoadjuvant 
therapy trials in gastric cancer demonstrating survival is associated with pathologic response to 
pre-operative therapy5,15. In an analysis of patients experiencing a pathologic complete response 
(pCR) to neoadjuvant therapy, Fields et al. demonstrated recurrence rates at 5 years were 
significantly lower for patients who achieved a pCR versus a non-pCR (27% vs. 51%)16. Taken 
together, these data suggest that effective systemic and regional therapy combined may improve 
survival in patients with cytologic M1 disease if a pathologic complete response to therapy can be 
achieved.
1.2.1
Rationale for Palliative Gastrectomy and Regional Therapy in Gastric Cancer 
We hypothesize that gastrectomy to remove the primary tumor combined with multi-modality 
treatment of microscopic peritoneal metastasis may improve survival in patients with gastric 
cancer. The clinical indications for palliative gastrectomy include relief of obstruction and 
refractory bleeding. An oncologic justification for palliative gastrectomy is wanted despite an 
association with improved survival reported in multiple retrospective studies.17,18 Hartgrink et al. 
reported an overall survival advantage associated with gastrectomy in patients with non-curable 
gastric cancer that was evident only in patients with one site (versus multiple sites) of metastasis, 
thus implicating differential tumor biology.17 To date, a single prospective randomized trial has 
been performed to evaluate the role of palliative gastrectomy (without metastasectomy) prior to 
systemic therapy for patients with limited (solitary site) gastric cancer metastasis.19 Although there 


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was no difference in survival between treatment arms, the study did not allow for metastasectomy 
in these patients with limited metastatic disease. Resection of the primary tumor in the setting of 
metastatic disease has been studied prospectively, notably in renal cell carcinoma, and 
demonstrated improved overall survival for patients undergoing nephrectomy and systemic 
therapy compared to systemic therapy alone.20,21 Some explanations of these findings echo the 
classic ‘seed and soil’ hypothesis of Paget, the proponents of which contend that therapies should 
not only address the source of cancer cells (the ‘seed’), but also the unique microenvironment of 
different organs (the ‘soil’). In support of completely eliminating the ‘seed’, detection of 
circulating tumor cells after curative resection for colorectal cancer has been associated with worse 
cancer specific outcomes.22 In a study of metastatic colorectal cancer detection of circulating tumor 
cells in peripheral blood was associated with progression free survival in patients undergoing 
cytoreductive surgery and intraperitoneal chemotherapy.23 
Intraperitoneal (IP) drug delivery is an effective treatment strategy in certain solid tumors prone 
to peritoneal carcinomatosis. The rationale for regional chemotherapy to the peritoneal surfaces is 
to maximize drug delivery to affected sites of disease while increasing the therapeutic window by 
limiting systemic toxicity. Work performed at NCI and elsewhere has established the 
pharmacokinetic rationale for IP drug delivery24-26. Subsequent clinical studies have established 
IP chemotherapy as the optimal treatment for patients with ovarian carcinomatosis, primary 
peritoneal mesothelioma and appendiceal mucinous neoplasms27-29. A prospective study of 
cytoreductive surgery, gastrectomy and HIPEC with or without systemic chemotherapy in patients 
with metastatic gastric cancer was performed in the Surgery Branch by Rudloff et al30. Although 
underpowered, the study demonstrated that patients with peritoneal carcinomatosis and limited 
disease burden could achieve prolonged survival with cytoreduction, including gastrectomy, and 
IP chemotherapy.
In order to understand the potential role for regional therapy in patients with gastric cancer we 
performed a systematic review of the literature to identify studies that utilized adjuvant IP 
chemotherapy in gastric cancer. Our review encompassed 2,042 patients enrolled in phase II 
randomized controlled trials (RCTs; n=13) or high-quality comparative case control studies (n=4) 
that examined adjuvant IP chemotherapy for gastric cancer (Table 1: Systematic Review). 
Adjuvant IP chemotherapy was well-tolerated; the most common side effects reported were 
hematologic and infectious and there were no treatment-related mortalities reported in the IP 
therapy arms. Despite the heterogeneity of studies with respect to patient accrual, timing of IP drug 
delivery, and chemotherapy selection, several themes emerged. Primarily, there was an associated 
improvement in five-year overall survival in studies that administered adjuvant IP chemotherapy 
in any form. Furthermore, IP treatment appeared most beneficial when it was administered intra-
operatively. Figure 2 depicts the results of a random effects model that includes studies reporting 
five-year survival data. Although survival rates across studies varied, two systematic reviews have 
concluded the use of adjuvant IP chemotherapy for resectable gastric cancer is associated with 
improved survival39,40,41,42,43. 
While these data suggest an incremental benefit of intra-operative IP chemotherapy it is possible 
that enrichment for patients at highest risk for peritoneal carcinomatosis would show a clearer 
benefit of this strategy. Importantly, the majority of these randomized prospective studies were 
performed in Asia. The difference in gastric cancer-specific outcomes between Asian and Western 
patients is well-documented; therefore, the results of these trials must be viewed with caution44,45. 


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1.2.2
Drivers of Peritoneal Metastasis in Gastric Cancer
Gastric adenocarcinoma is a heterogeneous disease with various environmental and genetic 
predisposing factors. Comprehensive molecular analyses published in recent years have provided 
additional insight into distinct sub-classifications of gastric cancer based on unique molecular 
alterations46,47. These studies have revealed novel correlations of molecular subtypes with distinct 
tumor phenotypes and clinical outcomes47. Consequently, these provocative data are expected to 
aid in identification of novel therapeutic targets and patient-specific therapies. The proposed 
molecular sub-classifications of gastric cancer have yet to be validated prospectively, however, 
and are not currently applied to clinical decision making.
Peritoneal carcinomatosis is a particularly morbid and common feature of gastric 
adenocarcinomas. The association between diffuse-type tumor histology and increased rates of 
carcinomatosis is well-documented4. Somatic gene alterations that impair E-cadherin protein 
expression are also a recurring feature of sporadic diffuse-type gastric cancers48. Germline 
mutation in CDH1, the gene that encodes the cell-cell adhesion protein E-cadherin, results in a 
heritable form of diffuse-type gastric cancer that may aid our understanding of sporadic disease49. 
Even though disruption of cell-cell adhesion is cited as an initiating event in this histologic subtype, 
true drivers of tumor invasion and peritoneal metastasis have not been characterized.50,51 Better 
understanding of molecular alterations associated with unique patterns of metastasis may uncover 
key drivers of distinct malignant phenotypes 52. 
Currently, two biologic agents are approved for use in advanced gastric cancer: anti-VEGF and 
anti-HER2 antibodies. While anti-VEGF therapy is not based on known molecular alterations in 
gastric cancers, the over-expression of HER2 in about 20% of gastric adenocarcinomas forms the 
basis of its use in HER2+ metastatic disease. Even so, the clinical benefit of anti-HER2 therapy is 
associated with only a modest improvement in median survival of 2.7 months.53 Notably, diffuse-
type gastric cancers rarely overexpress HER2 compared to intestinal-type tumors (6.1% and 
31.8%, respectively) based on data from the ToGA trial54. Therefore, clinically meaningful and 
targeted therapy for diverse subtypes of gastric cancers is needed.
The Cancer Genome Atlas (TCGA) Research Network published a comprehensive analysis of 
gastric adenocarcinomas resulting in a proposed molecular sub-classification46. In their report the 
genomically stable (GS) subtype of cancers were majority (70%) diffuse-type histology and 
harbored frequent CDH1 mutations (37%). CDH1 germline mutations are linked to hereditary 
diffuse gastric cancer (HDGC), while sporadic forms of diffuse gastric cancer are marked by E-
cadherin loss through somatic mutation of CDH1 or promoter hypermethylation55,56. Recurrent 
mutations in RHOA also have been described in up to 25% of patients with diffuse gastric 
cancer51,57. RhoA, a GTPase encoded by RHOA, and a downstream effector, ROCK1 (Rho-
associated protein kinase 1), are regulators of cytoskeletal elements and cellular motility. The 
RHOA/ROCK1 signaling pathway is important also for epithelial-to-mesenchymal transition and 
is implicated in gastric cancer metastasis58-61. Work by Kakiuchi and colleagues was performed to 
explore possible driver mutations in diffuse-type gastric cancer (DGC)51. Whole-exome 
sequencing of DGC samples revealed 25.3% (22/87) of tumors with recurrent mutations in RHOA, 
with mutation hotspots affecting the protein at Tyr42, Arg5 and Gly17 residues. A similar RHOA 
mutation profile was reported by Wang and coworkers with a recurring hotspot altering Tyr42 
whereas no RHOA mutations seen in intestinal-type tumors57. The Tyr42 residue of RhoA is 


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important for interaction with effector molecules such as RhoGEF (Rho GDP/GTP-exchange 
factor) thus affecting downstream RhoA signaling.
Using a provisional TCGA data set accessed via cBioPortal, 289 samples of gastric 
adenocarcinoma with available sequencing data were queried for alterations in CDH1, RHOA, and 
ROCK162,63. Somatic alterations in CDH1, RHOA and ROCK1 were found in 25% (71/289) of 
tumors and there was a trend toward co-occurrence of CDH1 and RHOA mutations (Figure 3; 
these results are in whole based upon data generated by the TCGA Research Network: 
http://cancergenome.nih.gov/.) A similar finding by Kakiuchi et al. reported CDH1 mutations in 
32% (28/87) of diffuse cancers, and, along with the RHOA mutants, these alterations appeared 
almost exclusively in DGC when compared to a set of intestinal-type tumors51.  
The Asian Cancer Research Group (ACRG) selected 300 primary gastric cancer specimens to 
develop a molecular classification system47. Unlike the TCGA data set, these samples were 
uniformly obtained from patients operated at a single center in Korea. Four distinct subtypes of 
gastric adenocarcinoma were proposed: microsatellite instability (MSI), microsatellite 
stable/epithelial-to-mesenchymal 
transition 
(MSS/EMT), 
and 
MSS/TP53-activity 
high 
(MSS/TP53+) and MSS/TP53-activity low (MSS/TP53-). Clinical phenotypes were associated 
with molecular subtypes such that the MSS/EMT tumors occurred in younger patients and were 
majority (80%) diffuse-type histology. The MSS/EMT group also had substantially higher rates of 
peritoneal metastasis and worse overall survival compared to the other subtypes. Interestingly, 
CDH1 and RHOA mutations were not frequent in the MSS/EMT group, which is contrary to the 
TCGA findings in the genomically stable (GS) subtype. These differences indicate the MSS/EMT 
and TCGA GS subtypes are not equivalent and highlight the need for validation of the proposed 
molecular classifications of gastric cancer. 
Translational research efforts have been established in our branch to investigate drivers of 
peritoneal metastasis in gastric adenocarcinoma. Clinical protocols incorporating both sporadic 
and hereditary diffuse gastric cancers (HDGC) will be conducted in parallel to strengthen the 
search for key drivers of peritoneal metastasis. The current Phase 2 trial of heated intraperitoneal 
chemotherapy delivered to gastric cancer patients with positive peritoneal cytology is designed to 
determine overall survival in patients treated with this strategy. A concurrent protocol for patients 
with heritable gastric cancer syndromes is designed to study the natural history of these syndromes, 
characterize germline mutations, perform cancer risk-reducing surgery, and genotype-phenotype 
correlation. It is expected that patients who undergo risk-reducing total gastrectomy, in addition to 
those receiving gastrectomy and HIPEC on the current protocol, will provide a rare opportunity 
for detailed analysis of molecular changes associated with gastric cancer initiation, invasion and 
metastasis. 
The goal of the current protocol is to address the challenges outlined above; evaluate a strategy for 
treating gastric cancers with positive peritoneal cytology, validate molecular subtyping of gastric 
and associated peritoneal metastases, and discover key drivers of peritoneal tumor dissemination.


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Abbreviated Title: HIPEC for Gastric Cancer
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2
ELIGIBILITY ASSESSMENT AND ENROLLMENT
2.1
ELIGIBILITY CRITERIA
2.1.1
Inclusion Criteria
2.1.1.1
Patients must have histologically or cytologically confirmed gastric adenocarcinoma or 
gastroesophageal junction (Siewert I-III) adenocarcinoma confirmed by the Laboratory 
of Pathology, NCI.
2.1.1.2
Must have received systemic chemotherapy, minimum 3 months or maximum 6 months, 
prior to enrollment:

Systemic therapy should consist of at least fluoropyrimidine-based and/or platinum-
based chemotherapy.

Trastuzumab may be added for HER2-neu over-expressing cancers as clinically 
indicated.

Last dose of chemotherapy within 8 weeks of enrollment with recovery to Grade 1 from 
chemotherapy-related toxicities.

Documentation of chemotherapy administration must be obtained.
2.1.1.3
Sub radiographic and/or cytopathologic evidence of peritoneal carcinomatosis found at 
staging laparoscopy (see Table 2: Cytopathologic Analysis Definitions):

Documentation of cytopathologic diagnosis of malignant peritoneal cytology in the 
absence of disseminated peritoneal disease must be obtained. If cytologic analysis 
reveals atypical cells of undetermined significance, a repeat lavage with cytopathologic 
analysis will be performed and must demonstrate evidence of malignancy.

Limited peritoneal involvement (≤ P1 or PCI ≤ 10)64 found at staging laparoscopy or 
on final pathology that is deemed completely resectable is permitted (see Appendix 
C).
2.1.1.4
Age ≥ 18 years.  
2.1.1.5
ECOG performance status ≤ 2 (see Appendix A).
2.1.1.6
Patients must have normal organ and marrow function as defined below: 
hemoglobin 
> 8.0 g/dL
absolute neutrophil count
≥ 1,000/mcL
platelets
≥ 100,000/mcL
total bilirubin
within normal institutional limits
AST(SGOT)/ALT(SGPT)
≤ 2.5 X institutional upper limit of normal
creatinine
< 1.5 mg/dl
OR
eGFR (creatinine clearance)
≥ 60 mL/min/1.73 m2.


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Abbreviated Title: HIPEC for Gastric Cancer
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2.1.1.7
Physiologically able to undergo HIPEC and gastrectomy.
2.1.1.8
No history of malignancy within 2 years of enrollment except for basal cell carcinoma of 
the skin, squamous cell skin cancer or carcinoma in situ of the cervix. 
2.1.1.9
Ability of subject to understand and the willingness to sign a written informed consent 
document.
2.1.1.10 Previous exploratory laparotomy or laparoscopy with tissue biopsy or peritoneal lavage 
is permitted. (Prior Surgical Score, PSS, of 0 or 1)65.
2.1.1.11 Women of child-bearing potential and men must agree to use adequate contraception 
(hormonal or barrier method of birth control; abstinence) prior to study entry and for the 
duration of study participation.  Should a woman become pregnant or suspect she is 
pregnant while she or her partner is participating in this study, she should inform her 
treating physician immediately.
2.1.1.12 Subjects must agree to co-enrollment on the tissue collection protocol 13C0176, “Tumor, 
Normal Tissue and Specimens from Patients Undergoing Evaluation or Surgical 
Resection of Solid Tumors”.
2.1.2
Exclusion Criteria
2.1.2.1
Patients who are receiving any investigational agents.
2.1.2.2
Disseminated extra-peritoneal or solid organ metastases:

Includes carcinomatosis associated with clinically or radiographically evident ascites 
(greater than 500 cc).

Excludes greater omentum and ovarian metastases.
2.1.2.3
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study requirements.
2.1.2.4
Pregnant women are excluded from this study because HIPEC and gastrectomy have not 
been studied in pregnant women and has the potential for teratogenic or abortifacient 
effects.  Because there is an unknown but potential risk for adverse events in nursing 
infants secondary to treatment of the mother with HIPEC and gastrectomy, breastfeeding 
should be discontinued if the mother is treated on this study.
2.1.2.5
HIV-positive patients may be considered for this study only after consultation with a 
NIAID physician.
2.1.3
Recruitment Strategies
This protocol may be abstracted into a plain language announcement posted on NIH websites 
and on NIH social media platforms.
2.2
SCREENING EVALUATION
2.2.1
Screening Activities Performed Prior to Obtaining Informed Consent
Minimal risk activities that may be performed before the subject has signed a consent include the 
following: 

Email, written, in person or telephone communications with prospective subjects. 

Review of existing medical records to include H&P, laboratory studies, etc.  


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Abbreviated Title: HIPEC for Gastric Cancer
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
Review of existing MRI, x-ray, or CT images.

Review of existing photographs or videos.

Review of existing pathology specimens/reports from a specimen obtained for diagnostic 
purposes.
A waiver of consent for these activities has been requested in Section 10.6.1.
2.2.2
Screening Activities Performed After a Consent for Screening Has Been Signed
The following activities will be performed only after the subject has signed the consent for this 
study for screening. Assessments performed at outside facilities or on another NIH protocol within 
the timeframes below may also be used to determine eligibility once a patient has signed the 
consent.  
2.2.2.1
Within 8 Weeks Prior to Being Registered for Study Treatment (Unless Otherwise 
Indicated)

History and Physical Evaluation:
o
Complete medical history and physical examination (including height, weight, vital 
signs, EKG, and ECOG performance status). 
o
Consultation with NIAID physician in HIV positive subjects.

Laboratory Evaluation:

Hematological Profile: CBC with differential and platelet count.

Biochemical Profile: Acute, Hepatic, Mineral Panels 

Serum or urine pregnancy test for female participants of childbearing age and anatomic 
ability (for eligibility).

HIV test, Hepatitis B surface antigen, and Hepatitis C antibody.

Laparoscopic Staging (if clinically indicated) 
Note: Patients undergoing re-staging laparoscopy at an outside facility must have operative 
documentation and pathology slides/tissue submitted for review CT-CAP and PET scan of 
chest, abdomen and pelvis.

Histologic Confirmation (at any time point prior to initiation of study therapy, if clinically 
indicated). 
Note: A block or unstained slides of primary or metastatic tumor tissue will be required 
from each participant to confirm diagnosis with analysis being performed by the 
Laboratory of Pathology, NIH. 

CT chest, abdomen, and pelvis (C/A/P) or PET/CT 
2.3
PARTICIPANT REGISTRATION AND STATUS UPDATE PROCEDURES
Registration and status updates (e.g., when a participant is taken off protocol therapy and when a 
participant is taken off-study) will take place per CCR SOP ADCR-2: CCR Participant 
Registration & Status Updates found here. 


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Abbreviated Title: HIPEC for Gastric Cancer
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2.3.1
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical trial but are 
not subsequently assigned to the study intervention or entered in the study. A minimal set of screen 
failure information is required to ensure transparent reporting of screen failure participants, to meet 
the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, screen 
failure details, eligibility criteria, and any serious adverse event (SAE).
2.3.2
Treatment Assignment Procedures
Cohorts
Number
Name
Description
A
Cohort A
Patients with gastric adenocarcinoma or 
gastroesophageal junction (Siewert I-III) 
adenocarcinoma.
Arms
Number
Name
Description
1
HIPEC with 
gastrectomy 
Patients will undergo HIPEC with gastrectomy.
Arm Assignment
Patients in Cohort A will be directly assigned to Arm 1.
2.4
BASELINE EVALUATION
Note: Tests listed below that were performed within the appropriate timeframe at screening need 
not be repeated.
2.4.1
Within 8 Weeks Prior to Treatment with HIPEC

Patients will need documentation of peritoneal re-staging by CT C/A/P or PET/CT, 
and/or laparoscopy. 
2.4.2
Within 4 Weeks Prior to Treatment with HIPEC

History and Physical Examination (if clinically indicated):
o
Complete medical history and physical examination (including vital signs, 
height and weight, as well as EKG and ECOG assessment, and review of 
systemic treatment records).

Dietary Assessment (if clinically indicated).

Concurrent Medication (when clinically indicated).

Laboratory Evaluation (if clinically indicated):
o
General Labs:

CBC with platelets 


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Abbreviated Title: HIPEC for Gastric Cancer
Version Date: 12/28/2021

Chem-20 equivalent (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, Total Protein, total CK. 

PT/PTT & INR.
o
Nutrition Labs: 

C-reactive protein, Hg A1c, Ferritin, Prealbumin, Thiamine, Iron panel, 
Vitamin B12, Methlymalonic acid, Zinc, 25-hydroxy Vitamin D
o
Urinalysis 
o
CEA, CA 19-9, CA 15-3, CA 125, CA 27-29 tumor markers

CT C/A/P or PET/CT

Quality of Life Questionnaire (3.4.6).
2.4.3
Pre-Operation Visit (Prior to Treatment with HIPEC)

Beta HCG for women of child-bearing potential prior to operation only (within 72 
hours prior to initiating treatment).
3
STUDY IMPLEMENTATION
3.1
STUDY DESIGN
This is a Phase II trial designed to determine the efficacy of heated intraperitoneal chemotherapy 
(HIPEC) in patients with gastric cancer and associated positive peritoneal cytology. Patients with 
a diagnosis of or clinical suspicion of gastric malignancy may undergo screening and initial 
evaluation on the ‘Profiling of Gastric Tumors’ protocol (17C0044). All patients will be discussed 
at a regular multidisciplinary gastrointestinal malignancies conference.
Patients will receive systemic chemotherapy by their treating oncologist for a minimum of 3 
cycles. Staging imaging studies and laparoscopy will be performed to rule out progression of 
disease. After these staging studies, if patients meet eligibility they will be enrolled on the current 
protocol. Patients will undergo standard pre-operative evaluation and undergo HIPEC with 
gastrectomy. Patients found to have distant or diffuse peritoneal carcinomatosis (≥ P2 or Peritoneal 
Cancer Index, PCI, > 10) that cannot be completely resected will undergo biopsy to document 
disease, and will not receive the assigned treatment. Although it is anticipated to be an uncommon 
occurrence, patients who experience refractory bleeding or gastric outlet obstruction may be 
offered palliative surgical intervention even if they are unable to receive HIPEC and resection. 
All tumors will be pathologically staged according to American Joint Committee on Cancer 7th 
edition criteria66. Post-operatively, systemic therapy will be administered at the discretion of the 
treating medical oncologist.
3.2
DRUG ADMINISTRATION
Intraperitoneal chemotherapy will be delivered via a closed perfusion circuit in the Clinical Center 
operating room under the direction of the Principal Investigator or designated Associate 
Investigators. Body surface area for each patient will be calculated.


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Abbreviated Title: HIPEC for Gastric Cancer
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3.2.1
Cisplatin and Mitomycin
Cisplatin (90 mg/m2) and mitomycin C 10 mg/m2 will be diluted in 1L of 1.5% dextrose dialysis 
solution and administered via circuit to the peritoneal cavity.
Note: Cisplatin and mitomycin C may be provided separately and may be provided in a 
different diluent if 1.5% dextrose dialysis solution is not available. The alternate diluent is 
described in Sections 12.1 and 12.2.
3.2.2
Sodium Thiosulfate
Sodium thiosulfate will be administered by continuous intravenous infusion starting immediately 
prior to the perfusion and continuing for a total of 12 hours.

A loading dose of 7.5 gm/m2 of sodium thiosulfate will be diluted in 150 cc of 0.9% 
sodium chloride for injection. This loading dose will be infused over 20 minutes 
beginning with the addition of cisplatin to the peritoneal perfusion circuit.

Immediately following this bolus dose an additional 25.56 gm/m2 of sodium thiosulfate 
will be diluted in 1000 cc of 0.9% sodium chloride for injection for a maintenance 
infusion of 2.13 gm/m2 per hour for 12 hours. The maintenance infusion will be 
delivered by infusion pump.


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Abbreviated Title: HIPEC for Gastric Cancer
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3.3
STUDY CALENDAR
Post-Discharge Visits/Follow-Up2 
(Months)
Screening
Baseline   Operation
Post-Op 
Care
(While 
in ICU)
1
3
6
9
12
15
18
21
24
Semi-
Annual 
Follow Up 
(Semi-
Annually 
for Years 
3-5)
Annual 
Follow 
Up
(Annually 
after Year 
5)4
Confirmation of 
Pathology
x
Concurrent 
Medications3
x
ECOG 
Performance 
Status3
x
x1
x
x
x
x
x
x
x
x
x
x
x
Physical 
Examination 
(Including Vital 
Signs, Weight and 
Height)
x
x1
x
x
x
x
x
x
x
x
x
x
Dietary 
Assessment3
x
x
x
x
x
x
x
x
x
x
x
x
x
H&P3
x
x1
Focused H&P3
x
x
x
x
x
x
x
x
x
x
x


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Abbreviated Title: HIPEC for Gastric Cancer
Version Date: 12/28/2021
Post-Discharge Visits/Follow-Up2 
(Months)
Screening
Baseline   Operation
Post-Op 
Care
(While 
in ICU)
1
3
6
9
12
15
18
21
24
Semi-
Annual 
Follow Up 
(Semi-
Annually 
for Years 
3-5)
Annual 
Follow 
Up
(Annually 
after Year 
5)4
Tumor Biopsy3
x
x1
x
CT C/A/P or
PET-CT2
(MRI if CT imaging 
contraindicated)
x
x1
x
x
x
x
x
x
x
x
x
x
x
General Labs 
(listed in Sections 
2.4.2 and 3.4) 3
x
x1,3
x
x
x
x
x
x
x
x
x
x
x
x
HIV, HepB, HepC
x
Nutrition Labs (as 
listed in Section 
2.4.2) 3
x
x
x
x
x
x
x
x
x
x
x
Tumor Markers 
(Section 2.4.2) 3
x
x
Urinalysis3
x
Pregnancy Test
x
x


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Abbreviated Title: HIPEC for Gastric Cancer
Version Date: 12/28/2021
Post-Discharge Visits/Follow-Up2 
(Months)
Screening
Baseline   Operation
Post-Op 
Care
(While 
in ICU)
1
3
6
9
12
15
18
21
24
Semi-
Annual 
Follow Up 
(Semi-
Annually 
for Years 
3-5)
Annual 
Follow 
Up
(Annually 
after Year 
5)4
EKG
x
x1
QOL 
Questionnaire2
x
x
x
x
x
x
x
x
x
x
Consultation with 
NIAID Physician 
in HIV Positive 
Subjects
x
NIH Advanced 
Directives Form5
x
1 Does not need to be repeated at Baseline if test was performed on Screening within the defined timeline (see Section 2.4).
2 Post-discharge visits/follow-up will include CT C/A/P or PET/CT as indicated in Section 3.4.5; completion of QOL questionnaires 
as indicated in Section 3.4.6; follow-up physical examination and labs as clinically indicated per Section 3.4.5. Note: For patients who 
have documented disease progression after HIPEC refer to Section 3.4.5.
3 If clinically indicated.
4 If patients are not able to come to NIH after 5 years or have documented disease progression, they will be followed by phone contact 
or other NIH approved remote platforms (used in compliance with policy, including HRPP Policy 303) annually for survival, 
performance status, new cancer treatment (refer to Section 3.4.5).


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Abbreviated Title: HIPEC for Gastric Cancer
Version Date: 12/28/2021
5 As indicated in Section 10.3, all subjects will be offered the opportunity to complete an NIH advanced directives form. This should 
be done preferably at baseline but can be done at any time during the study as long as the capacity to do so is retained. The completion 
of the form is strongly recommended, but is not required.


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Abbreviated Title: HIPEC for Gastric Cancer
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3.4
SURGICAL GUIDELINES 
3.4.1
Preoperative Patient Management
Patients will receive standard preoperative care as appropriate to the planned surgical intervention 
and the patient’s underlying health status. This will include:

Clear liquid diet the day prior to operation, with or without additional bowel preparation.

Hibiclens shower the night before operation.

Preoperative IV antibiotics administered within 2 hours prior to operation start.

Sequential compression devices will be placed on the lower extremities prior to induction 
of general anesthesia.

Subcutaneous heparin administration for venous thromboembolism prophylaxis just prior 
to operation start.
3.4.2
Patient Management in the Operating Room
3.4.2.1
At Operation (As Clinically Indicated)

Patients will undergo resection of the primary tumor along with a modified D2 
lymphadenectomy will be performed; this implies nodal dissection of stations 1–11 without 
obligatory splenectomy or distal pancreatectomy. 

Local invasion of adjacent structures is not a contraindication to resection.

In patients at risk for splenectomy (proximal T3-T4 lesions) immunization against 
pneumococcus, meningococcus and haemophilus influenzae will be administered pre-
operatively or > 1 week after operation for patients in whom splenectomy was necessary 
at time of operation. 

If limited (< P1, or PCI < 10) peritoneal tumor implants are encountered, a complete 
resection will be performed. 
3.4.2.2
HIPEC

Peritoneal perfusion may be performed via open or closed technique, which is described 
hereafter.

For closed technique, two large bore catheters will be placed into the abdomen, one over 
the right liver and one in the pelvis and the catheters connected to a perfusion circuit.

Drug administration (Section 3.2) will be performed via the perfusion circuit.

Intravenous thiosulfate will be administered prior to cisplatin administration and followed 
by continuous infusion as per Section 3.2.

The perfusion flow rate will be maintained at least 1 L/min and a perfusate volume will 
be maintained which moderately distends the abdominal cavity correlating with intra-
abdominal pressures of 5–15 mmHg.

Stable perfusion parameters are obtained and inflow is set to a target of 41 degrees 
Celsius prior to starting the clock for perfusion time; the perfused temperature will not 
exceed 42 degrees Celsius.

Perfusion will be continued for 60 minutes. During the perfusion, constant physical 
manipulation of the abdomen (shaking) will be maintained to assure even distribution of 
perfusate. 

Peritoneal temperature will be measured continuously. 


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Abbreviated Title: HIPEC for Gastric Cancer
Version Date: 12/28/2021

The patient’s core temperature will be measured with esophageal temperature probe and 
maintained at less than 41 degrees Celsius using a cooling blanket and ice packs around 
the legs and head.

At the end of perfusion, the circuit will be flushed with saline solution to irrigate the 
perfusate from the abdominal cavity; the abdominal cavity will be lavaged as needed.
3.4.2.2.1 Type of Primary Tumor Resection (As Clinically Indicated)
o
For tumors of the gastric body or antrum, a subtotal gastrectomy will be 
performed. This will include ligation of the right gastric, right gastroepiploic, and 
left gastric arteries (for proximal subtotal resection) at their origins with removal 
of associated lymphoid tissue. The lesser and greater omentum will be removed.
o
For proximal gastric tumors a total gastrectomy with 2–4 cm esophageal margin 
will be performed when possible.
o
For GE junction tumors a standard esophagogastrectomy (Ivor Lewis) will be 
performed.
3.4.2.2.2 Lymph Node Dissection (As Clinically Indicated)
o
Perigastric lymph nodes (stations 1, 3 and 5) and greater curve lymph nodes 
(stations 2, 4 and 6) will be removed as part of a D1 lymphadenectomy; the lymph 
nodes around the left gastric artery (station 7), common hepatic artery (station 8), 
celiac artery (station 9) and splenic artery (stations 10 and 11) will be removed as 
part of a modified D2 lymphadenectomy, without obligatory splenectomy or 
distal pancreatectomy.
o
The extent of the D2 lymphadenectomy will be determined by the operating 
surgeon depending on tumor characteristics and whether nodal regions can be 
accessed safely while sparing the spleen and distal pancreas. 
3.4.2.2.3 Peritoneal Metastasectomy (As Clinically Indicated)
o
For patients with visible peritoneal metastases (small disease burden, ≤ P1 or PCI 
< 10) without massive ascites, all visible disease will be resected. Partial (limited) 
peritonectomy will be performed for these patients as indicated by visible disease.
o
Any omental implants will be removed as part of the omentectomy as described 
with the gastrectomy or esophagogastrectomy procedure.
3.4.3
Postoperative Care
3.4.3.1
Patient Monitoring 

The patients will be monitored in the Intensive Care Unit for no less than 12 hours after 
surgical resection. Routine ICU monitoring of vital signs will be performed according to 
the patient’s clinical status. While in the ICU, an attempt to keep urine output greater 
than 100 cc/hour will be made when physiologically feasible until the sodium thiosulfate 
is completed. 

Patients will be discharged from the ICU at the discretion of the treating surgeon and in 
accordance with the institution policies. 

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). 


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Abbreviated Title: HIPEC for Gastric Cancer
Version Date: 12/28/2021

Patients will receive routine post-operative care; early ambulation will be encouraged. 

Laboratory evaluations (as clinically indicated) will include: 
o
CBC, platelets, acute care, mineral and hepatic panel on post-operative days 1 
through 3, and then as clinically indicated until discharge. 
o
Patients will be transfused as appropriate to maintain a hemoglobin greater than or 
equal to 8 g/dl.
o
Tumor markers (CEA, CA 19-9, CA 15-3, CA 125, CA 27-29) for new baseline 
will be obtained within 5 days of discharge.  
o
Imaging studies will be obtained as clinically indicated. 
3.4.4
Discharge (As Clinically Indicated)

Total hospitalization may be approximately 7-21 days. 

Patients who are discharged within this time frame should be able to tolerate an oral diet 
with or without dietary supplements. 

Patients who have a prolonged hospitalization may be discharged with home 
rehab/physical therapy and/or the addition of enteral nutritional support via a feeding 
tube.

Patients may require evaluation by their referring physician following discharge; any 
clinically indicated laboratory testing obtained locally will be faxed to the Research 
Nurse. 
3.4.5
Post-Discharge/Follow-Up 
3.4.5.1
For Patients Who Return to the NIH Clinical Center

Patients will return to the NIH CC approximately 1, 3, 6, 9, 12, 15, 18, 21 and 24 months 
from the date of operation, and then every 6 months for years 3-5, and yearly thereafter 
except where otherwise indicated. Follow up visits may vary +/- 2 weeks for the first 2 
years, and +/- 4 weeks thereafter. At these time points patients will undergo:
o
Physical Examination including ECOG as clinically indicated.
o
Dietary Assessment as clinically indicated.
o
CT C/A/P or PET/CT, except at the 1-month follow-up.
o
General Labs as clinically indicated (refer to list in Section 3.4.3.1). 
o
Nutrition Labs as clinically indicated (refer to Section 3.3). 
o
Completion of QOL questionnaires per schedule in Section 3.4.6.
Note: Patients with documented disease progression after HIPEC will only be followed 
thereafter by phone, videocall or other NIH approved remote platform (used in 
compliance with policy, including HRPP Policy 303) annually for survival, performance 
status, and new cancer treatment.
3.4.5.2
For Patients Who Are Unable or Unwilling to Return to the NIH Clinical Center

Patients who are unable or unwilling to return to the CC for follow up evaluation will be 
followed by telephone, videocall or other NIH approved remote platform contact (used in 
compliance with policy, including HRPP Policy 303). 

The following information may be obtained:
o
Summary of treatment received since the previous contact as clinically indicated.
o
Estimation of ECOG status as clinically indicated.


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Abbreviated Title: HIPEC for Gastric Cancer
Version Date: 12/28/2021

Request for imaging studies, physical exam documentation and laboratory reports to be 
sent to the PI, as clinically indicated.
3.4.6
Measurement of Health-Related Quality of Life for Research
For patients fluent in English, Quality of Life questionnaires (QOL) will be completed at the pre-
treatment evaluation prior to HIPEC (baseline), at 1 month, 3 months and then every 3 months (+/- 
2 weeks) for 2 years. 
Patients will be informed of the details of the QOL part of this study and reassured that their 
decision to participate will not have an effect on the application of the treatment intervention. 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.
We will use tools specifically developed for assessment of QOL in gastric cancer patients: FACT-
Ga (Appendix B)67. Measures will be initially administered by an Associate Investigator Research 
Nurse or designee. The Research Nurse or designee 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 clipboard and pencil. QOL data 
will be collected in stored in Labmatrix. If it becomes available, electronic versions of QOL 
questionnaires will be developed with the assistance of Jason Levine, MD, and will be offered to 
patients via secure, web-based application. 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.
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.
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. Patients may complete questionnaires electronically or 
by phone, videocall or other NIH approved remote platforms (used in compliance with policy, 
including HRPP Policy 303) as applicable


26
Abbreviated Title: HIPEC for Gastric Cancer
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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 3.4.5.
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 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 will be phoned again.
3.5
COST AND COMPENSATION 
3.5.1
Costs
NIH does not bill health insurance companies or participants for any research or related clinical 
care that participants receive at the NIH Clinical Center. If some tests and procedures performed 
outside the NIH Clinical Center, participants may have to pay for these costs if they are not covered 
by insurance company. Medicines that are not part of the study treatment will not be provided or 
paid for by the NIH Clinical Center.    
3.5.2
Compensation
Participants will not be compensated on this study.
3.5.3
Reimbursement 
The NCI will cover the costs of some expenses associated with protocol participation.  Some of 
these costs may be paid directly by the NIH and some may be reimbursed to the 
participant/guardian as appropriate.  The amount and form of these payments are determined by 
the NCI Travel and Lodging Reimbursement Policy. 
3.6
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA
Prior to removal from study, effort must be made to have all subjects complete a safety visit 
approximately 30 days following the last dose of study therapy.
3.6.1
Criteria for Removal from Protocol Therapy

Completion of protocol therapy

Progressive disease

Participant requests to be withdrawn from active therapy

Investigator discretion

Positive pregnancy test
3.6.2
Off-Study Criteria

Participant requests to be withdrawn from study

Investigator discretion

Screening failure


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
Lost to follow-up

Death

PI decision to end the study
3.6.3
Lost to Follow-Up
A participant will be considered lost to follow-up if he or she fails to return for 4 scheduled visits 
and is unable to be contacted by the study site staff. 
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit:

The team will attempt to contact the participant and reschedule the missed visit within 
2 weeks and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain if the participant wishes to and/or should continue in the study.

Before a participant is deemed lost to follow-up, the investigator or designee will make 
every effort to regain contact with the participant (where possible, 3 telephone calls 
and, if necessary, an IRB approved certified letter to the participant’s last known 
mailing address or local equivalent methods). These contact attempts should be 
documented in the participant’s medical record or study file. 

Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up.
4
CONCOMITANT MEDICATIONS/MEASURES
During the post-operative period, patients will receive all standard of care supportive measures, 
including possible nasogastric tube drainage and bowel rest for ileus, pulmonary toilet teaching 
and incentive spirometry to prevent atelectasis, transfusions, and antibiotics as indicated. 
Treatment for Helicobacter pylori will be managed according to standard of care when it is first 
diagnosed, either at time of initial diagnosis of gastric cancer or at time of surgical intervention. 
After standard of care medical therapy, follow up testing for eradication will be done either through 
repeat pathologic analysis (i.e., via the surgical specimen) or via stool antigen testing.
5
CORRELATIVE STUDIES
5.1
 BIOSPECIMEN COLLECTION AND PROCESSING FOR RESEARCH
Patients will be co-enrolled on protocol 13C0176. All research specimens will be collected, 
stored, tracked and disposed of as specified in protocol 13C0176.
All correlative/exploratory studies will be done as indicated on protocol 13C0176. No correlative 
studies will be done on protocol 17C0070. 
Note: See Appendix D for a general reference of specimens and collection timepoints, noting 
that this information is only to be used as an overview for reference purposes; all biospecimens 
will be collected as indicated on 13C0176.


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6
DATA COLLECTION AND EVALUATION 
6.1
DATA COLLECTION
For the purposes of the research and correlation with clinical outcomes, demographic information, 
histology, operative and peri-operative interventions, pathologic findings, laboratory and imaging 
parameters (performed as part of routine or protocol specified patient care) may be collected on 
this study. The PI will be responsible for overseeing entry of data into a 21 CFR Part 11-compliant 
data capture system provided by the NCI CCR and ensuring data accuracy, consistency and 
timeliness. The principal investigator, associate investigators/research nurses and/or a contracted 
data manager will assist with the data management efforts. Primary and final analyzed data will 
have identifiers so that research data can be attributed to an individual human subject participant.
All adverse events, including clinically significant abnormal findings on laboratory evaluations, 
regardless of severity, will be followed until return to baseline or stabilization of event. 
Document AEs from the first study intervention (pre-operation visit) through 30 days after 
removal from study treatment or until off-study, whichever comes first. Beyond 30 days after the 
last dose of study therapy, only adverse events which are serious and related to the study 
intervention need to be recorded. 
End of Study Procedures: Data will be stored according to HHS, FDA regulations and NIH 
Intramural Records Retention Schedule as applicable. 
Loss or Destruction of Data: Should we become aware that a major breach in our plan to 
protect subject confidentiality and trial data has occurred, this will be reported expeditiously per 
requirements in Section 7.2.1. 
6.1.1
Routine Data Collection
Following enrollment and for the duration of the study, graded adverse events will be described 
in the source documents, reviewed by the designated research nurse, and captured in C3D unless 
otherwise indicated below. 
Note: No Grade 1 adverse events will be recorded. 
6.1.1.1
Concomitant medications:

Only those medications that the patient is taking at baseline on a routine basis or 
medications that cause an AE will be captured. (Thus, one time medications, PRN 
medications, and medications given to treat adverse events will not be captured.)
6.1.1.2
Laboratory Events
Laboratory events will be described in the source documents and captured in C3D as follows:

During hospitalization for the HIPEC procedure, only the following labs will be 
updated into C3D:
o
Admission labs, 
o
First morning labs drawn after 4:00 AM, and 
o
Labs that support the diagnosis of a reportable event.

In the immediate post-operative period, only the following values will be captured 
(including laboratory values obtained at sites other than the NIH Clinical Center):


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o
Hemoglobin, total white blood cell count, absolute neutrophil count, platelet 
count
o
PT, PTT, or INR
o
Creatinine, ALT, AST, total and direct bilirubin

Any unexpected laboratory abnormality ≥ Grade 2 possibly, probably or definitely related 
to the surgical intervention. 
6.1.1.3
Exceptions to Adverse Event Recording
An abnormal laboratory value will be considered an AE if the laboratory abnormality is 
characterized by any of the following:
•
Results in discontinuation from the study.
•
Is associated with clinical signs or symptoms. 
•
Is associated with death or another serious adverse event, including hospitalization. 
•
Is judged by the Investigator to be of significant clinical impact.
•
If any abnormal laboratory result is considered clinically significant, the investigator will 
provide details about the action taken with respect to the test drug and about the patient’s 
outcome.
Non-laboratory, non-concomitant medication events that will be captured only in the source 
documents:

During hospitalization for surgical resection/HIPEC
o
Grade 2 events except unexpected events that are possibly, probably or 
definitely related to the research.

Post-operative recovery phase (following discharge)
o
Grade 2 events except unexpected events that are possibly, probably or 
definitely related to the research.
o
Note: Events that result in hospitalization for convenience will not be 
recorded.
6.2
DATA SHARING PLANS
6.2.1
Human Data Sharing Plan
What data will be shared?
I will share human data generated in this research for future research as follows:

Coded, linked data in a NIH-funded or approved public repository.

Coded, linked data in another public repository.

Coded, linked data in BTRIS (automatic for activities in the Clinical Center).

Identified or coded, linked data with approved outside collaborators under appropriate 
agreements.
How and where will the data be shared? 
Data will be shared through:


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
An NIH-funded or approved public repository; clinicaltrials.gov.

Another public repository.

BTRIS (automatic for activities in the Clinical Center). 

Approved outside collaborators under appropriate individual agreements.

Publication and/or public presentations.
When will the data be shared? 

Before publication.

At the time of publication or shortly thereafter.
6.2.2
Genomic Data Sharing Plan
Genomic testing will not be done under this protocol. 
6.3
RESPONSE CRITERIA
For the purposes of this study, patients should be re-evaluated for progression of disease at 3, 6, 
9, 12, 15, 18, 21, 24 months and semi-annually (every 6 months) during the 3rd, 4th and 5th years, 
and then every year after that until off-study.  Radiographic or clinical evidence of progression of 
disease will be confirmed, when necessary, by tissue biopsy.
Intraperitoneal progression of disease will be determined by radiographic evidence of new, large 
volume ascites with or without associated peritoneal nodularity or thickening. This may be 
confirmed by PET imaging and/or cytopathology or histopathology obtained by percutaneous 
biopsy. 
Extraperitoneal progression of disease will be confirmed based on characteristic radiographic 
findings (CT, MRI, and/or PET) and confirmed when indicated by percutaneous tissue biopsy.
Local recurrences will be confirmed endoscopically when necessary.
6.3.1
Methods for Evaluation of Measurable Disease
Chest x-ray:  Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung.  However, CT is preferable. 
Conventional CT and MRI:  This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm or less.  If CT scans have slice thickness 
greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness.  
MRI is also acceptable in certain situations (e.g., for body scans).  
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which greatly 
impact image quality, lesion conspicuity, and measurement.  Furthermore, the availability of 
MRI is variable globally.  As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type and site of disease.  
Furthermore, as with CT, the modality used at follow-up should be the same as was used at 
baseline and the lesions should be measured/assessed on the same pulse sequence.  It is beyond 
the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all 
scanners, body parts, and diseases.  Ideally, the same type of scanner should be used and the 


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image acquisition protocol should be followed as closely as possible to prior scans.  Body scans 
should be performed with breath-hold scanning techniques, if possible.
PET-CT:  At present, the low dose or attenuation correction CT portion of a combined PET-CT 
is not always of optimal diagnostic CT quality for use with RECIST measurements.  However, if 
the site can document that the CT performed as part of a PET-CT is of identical diagnostic 
quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be 
used for RECIST measurements and can be used interchangeably with conventional CT in 
accurately measuring cancer lesions over time.  Note, however, that the PET portion of the CT 
introduces additional data which may bias an investigator if it is not routinely or serially 
performed.  
Ultrasound:  Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement.  Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 
next.  If new lesions are identified by ultrasound in the course of the study, confirmation by CT 
or MRI is advised.  If there is concern about radiation exposure at CT, MRI may be used instead 
of CT in selected instances.
Endoscopy, Laparoscopy:  Such techniques may be useful to confirm progression of disease 
when images are captured and/or biopsies are obtained.
Tumor markers:  Tumor markers alone cannot be used to assess response.  If markers are initially 
above the upper normal limit, they must normalize for a patient to be considered in complete 
clinical response.  Specific guidelines for both CA-125 response (in recurrent ovarian cancer) 
and PSA response (in recurrent prostate cancer) have been published [JNCI 96:487-488, 2004; J 
Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 2008].  In addition, the 
Gynecologic Cancer Intergroup has developed CA-125 progression criteria which are to be 
integrated with objective tumor assessment for use in first-line trials in ovarian cancer [JNCI 
92:1534-1535, 2000].
Cytology, Histology:  These techniques can be used to confirm progression or recurrence of 
disease. 
The cytological confirmation of the neoplastic origin of any ascites that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease.
FDG-PET:  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis of 
FDG-PET imaging can be identified according to the following algorithm: 
a.
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion.
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If 
the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 


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additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal 
FDG-PET scan).  If the positive FDG-PET at follow-up corresponds to a pre-existing 
site of disease on CT that is not progressing on the basis of the anatomic images, this 
is not PD.
c.
FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy 
in cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring.  The use of FDG-PET in this circumstance should be prospectively 
described in the protocol and supported by disease-specific medical literature for the 
indication.  However, it must be acknowledged that both approaches may lead to false 
positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity.
 Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image.
6.3.2
Progression-Free Survival
Intraperitoneal PFS is defined as the duration of time from date of operation (HIPEC and 
gastrectomy) to the date of first observation of progressive disease within the peritoneal cavity 
(malignant ascites, peritoneal carcinomatosis), or death, whichever comes first. Extraperitoneal 
DFS i.e., anything other than peritoneal surface disease progression) is defined as the duration of 
time from date of surgery to the date of first observation of progressive disease at sites other than 
the peritoneal surface, such as the liver, intra-abdominal lymph nodes, abdominal wall soft 
tissues, and any other solid organs.
6.4
TOXICITY CRITERIA
The following adverse event management guidelines are intended to ensure the safety of each 
patient while on the study.  The descriptions and grading scales found in the revised NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE 
reporting.  All appropriate treatment areas should have access to a copy of the CTCAE version 
4.0.  A copy of the CTCAE version 4.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40). 
7
NIH REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN
7.1
DEFINITIONS
Please refer to definitions provided in Policy 801: Reporting Research Events found here. 
7.2
OHSRP OFFICE OF COMPLIANCE AND TRAINING/IRB REPORTING
7.2.1
Expedited Reporting
Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 
802: Non-Compliance Human Subjects Research found here. 
7.2.2
IRB Requirements for PI Reporting at Continuing Review
Please refer to the reporting requirements in Policy 801: Reporting Research Events found here.


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7.3
NCI CLINICAL DIRECTOR REPORTING
Problems expeditiously reported to the OHSRP in iRIS will also be reported to the NCI Clinical 
Director.  A separate submission is not necessary as reports in iRIS will be available to the Clinical 
Director.
In addition to those reports, all deaths that occur within 30 days after receiving a research 
intervention should be reported via email to the Clinical Director unless they are due to progressive 
disease.  
To report these deaths, please send an email describing the circumstances of the death to Dr. Dahut 
at NCICCRQA@mail.nih.gov within one business day of learning of the death.  
7.4
NIH REQUIRED DATA AND SAFETY MONITORING PLAN
7.4.1
Principal Investigator/Research Team 
The clinical research team will meet on a weekly basis when patients are being actively treated on 
the trial to discuss each patient. Decisions about dose level enrollment and dose escalation if 
applicable will be made based on the toxicity data from prior patients. 
All data will be collected in a timely manner and reviewed by the principal investigator or a lead 
associate investigator. Events meeting requirements for expedited reporting as described in Section 
7.2.1 will be submitted within the appropriate timelines.  
The principal investigator will review adverse event and response data on each patient to ensure 
safety and data accuracy. The principal investigator will personally conduct or supervise the 
investigation and provide appropriate delegation of responsibilities to other members of the 
research staff. 
8
STATISTICAL CONSIDERATIONS  
The primary objective of the trial is to determine if there is an improvement in overall survival 
(OS) in patients who have cytology positive (cyto+M1) gastric cancer when treated with systemic 
chemotherapy, HIPEC and gastrectomy compared to historical controls.  Outcomes reported for 
patients with positive peritoneal cytology suggest that the median OS for patients receiving 
systemic chemotherapy is approximately 14 months (range 13–15).10,13 It was also shown by 
Mezhir et al that patients who converted to negative cytology had an associated improvement in 
median overall survival of 24 months.  Thus, the goal will be to determine if the treatment strategy 
of systemic chemotherapy, HIPEC and gastrectomy could be associated with a 24-month median 
OS compared to 14 months median OS compared to these historical controls. 
With 37 evaluable patients receiving the proposed therapy with M1 disease, assuming accrual 
would take place over approximately 4 years, and that there would be at least 2 years of additional 
potential follow-up after the last patient has begun the HIPEC therapy, there would be 80% power 
to determine whether there is a difference between a median 14 month OS and an improved 24 
month OS after initiation of systemic treatment, with a one sided 0.10 alpha level test, using the 
method of Brookmeyer and Crowley (Brookmeyer R and Crowley, JJ. A confidence interval for 
the median survival time. Biometrics, 38, 29-41, 1982.). In practice, a Kaplan-Meier curve 
beginning at the initiation of systemic treatment and appropriate confidence intervals at selected 
time points will be provided to help interpret results relative to the expected results. At the 
conclusion of the trial, the patients with poorly differentiated tumors may be evaluated separately 


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from the remaining patients in order to obtain a preliminary estimate of the efficacy in these two 
subsets of patients. Evidence of benefit identified may be used to guide future studies evaluating 
this approach.
Intraperitoneal Progression Free Survival (iPFS) improvement is a secondary objective. Because 
there is inconsistent and sparse information in the literature about the iPFS of similar patients, the 
37 patients determined on the basis of estimating OS, will be used to generate an estimate of the 
iPFS rates at various time points. This information will be used to help guide subsequent study 
development as well as providing a publishable, reliable measure of this outcome. To the extent 
possible, the iPFS results may be informally compared to the few available results to describe the 
procedure’s potential benefit. Other secondary endpoints include distant disease free survival and 
treatment related morbidity. It is anticipated that 37 total patients can be accrued in approximately 
4 years. In order to allow for patients who are inevaluable for the determination of either endpoint, 
the accrual ceiling will be set at 40 patients.
If the trial is opened to multiple institutions to facilitate patient accrual, the biostatistician will be 
engaged first to discuss statistical implications or trial design.
9
COLLABORATIVE AGREEMENTS 
N/A
10 HUMAN SUBJECTS PROTECTIONS 
10.1 RATIONALE FOR SUBJECT SELECTION
Patients with a diagnosis of gastric cancer will be eligible for this study.  Eligibility assessment 
will be made solely on the patient’s medical status. Recruitment of patients on this study will be 
through standard CCR mechanisms. No special recruitment efforts will be conducted. 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 subjects 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 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.
10.2 PARTICIPATION OF CHILDREN
The surgical regimen used in this protocol is a major procedure which entails serious discomforts 
and hazards for the subject, such that fatal complications are possible. It is therefore only 
appropriate to carry out this experimental procedure in the context of life threatening gastric 
cancer. Since the efficacy of this experimental procedure is unknown, it does not seem reasonable 
to expose children to this risk without further evidence of benefit. Should results of this study 
indicate efficacy in treating gastric cancer, which is not responsive to other standard forms of 
therapy, future research can be conducted in the pediatric population to evaluate potential benefit 
in that patient population. 


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10.3 PARTICIPATION OF SUBJECTS UNABLE TO GIVE CONSENT
Adults unable to give consent are excluded from enrolling in the protocol.  However, re-consent 
may be necessary and there is a possibility, though unlikely, that subjects could become 
decisionally impaired. For this reason and because there is a prospect of direct benefit from 
research participation (Section 10.5), all subjects will be offered the opportunity to fill in their 
wishes for research and care, and assign a substitute decision maker on the “NIH Advance 
Directive for Health Care and Medical Research Participation” form so that another person can 
make decisions about their medical care in the event that they become incapacitated or cognitively 
impaired during the course of the study. Note: The PI or AI will contact the NIH Ability to Consent 
Assessment Team (ACAT) for evaluation to assess ongoing capacity of the subjects and to identify 
an LAR, as needed.
Please see Section 10.6.1 for consent procedure.
10.4 EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS
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, wound healing complications including fascial dehiscence, 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 unnecessary enterotomies or a bowel resection where feasible. In 
the case of intra-abdominal catastrophe after surgery, patients may require reoperation.
All care will be taken to minimize risks that may be incurred by tumor sampling. However, there 
are procedure-related risks (such as bleeding, infection and visceral injury) that will be explained 
fully during informed consent. If patients suffer any physical injury as a result of the biopsies, 
immediate medical treatment is available at the NCI’s Clinical Center in Bethesda, MD.  Although 
no compensation is available, any injury will be fully evaluated and treated in keeping with the 
benefits or care to which patients are entitled under applicable regulations.
10.4.1 Risks
10.4.1.1 HIPEC
The primary risks of intra-operative perfusion of the abdomen with chemotherapy are bleeding, 
infection, anastomotic leak, and enterocutaneous fistula. In addition, the chemotherapy may cause 
bone marrow suppression with decreased blood cell counts in the early post-operative phase.
10.4.1.2 Blood Collection
Risks of blood draws include pain and bruising in the area where the needle is placed, 
lightheadedness, and rarely, fainting. When large amounts of blood are collected, low red blood 
cell count (anemia) can develop. 
10.4.1.3 Urine Collection
There is no physical risk involved with urine collection. 


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10.4.1.4 Laparoscopy
Risks include bleeding, infection, hernia, injury to organs in the abdomen, abdominal 
inflammation, blood clots and adverse reactions to anesthesia.
10.4.1.5 Electrocardiogram (EKG)
This test is safe and side effects are unlikely, but it may be uncomfortable when the electrodes are 
taken off after the test is completed.
10.4.1.6 Questionnaires
Questionnaires may contain questions that are sensitive in nature. The patients are asked to only 
answer questions they are comfortable with.
10.4.1.7 Scans and Contrast
The most common discomfort is the length of time a patient must lay still during a scan. Patients 
may also become uncomfortable with the closed space of the machines. 
There is a small risk of reaction in scans involving contrast (including gadolinium). Common 
reactions include pain in the vein where the contrast was given, a metallic or bitter taste in the 
mouth, headache, nausea and a warm or flushing feeling that lasts from 1-3 minutes. In very rare 
cases, severe reactions that affect breathing, heart rhythm or blood pressure have occurred. 
Gadolinium for research MRI scans will not be given to patients who have impaired kidney 
function or who received gadolinium within the previous month.
An IV line may need to be inserted for administration of the contrast agent or anesthetic, which 
may cause pain at the site where the IV is placed and there is a small risk of bruising or infection.
10.4.1.8 Risks of Exposure to Ionizing Radiation
This research study involves the potential for up to 6 CT C/A/P or PET/CT scans, as well as a 
potential CT-guided biopsy for histologic confirmation, over the course of the first year on study. 
Subjects will be exposed to approximately 8.0 rem. This amount of radiation is above the guideline 
of 5 rem per year and will expose the subject to the roughly the same amount of radiation as 26.7 
years of background radiation. 
10.4.2 Potential Benefits
The potential benefit to subjects undergoing this treatment would be cure, or palliation at a 
minimum, in terms of preventing or delaying intra-abdominal tumor recurrence and metastases 
elsewhere which can be a devastating and painful source of symptoms and cause for demise.
10.5 RISKS/BENEFITS ANALYSIS
Patients with gastric cancer 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 HIPEC 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, 
although this protocol involves greater than minimal risk, it presents the prospect of direct benefit 
to individual subjects. 


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10.6 CONSENT PROCESS AND DOCUMENTATION
The informed consent document will be provided as a physical or electronic document to the 
participant or consent designee(s) as applicable for review prior to consenting. A designated study 
investigator will carefully explain the procedures and tests involved in this study, and the 
associated risks, discomforts and benefits. In order to minimize potential coercion, as much time 
as is needed to review the document will be given, including an opportunity to discuss it with 
friends, family members and/or other advisors, and to ask questions of any designated study 
investigator. A signed informed consent document will be obtained prior to entry onto the study.
The initial consent process as well as re-consent, when required, may take place in person or 
remotely (e.g., via telephone or other NIH approved remote platforms used in compliance with 
policy, including HRPP Policy 303) per discretion of the designated study investigator and with 
the agreement of the participant/consent designee(s).  Whether in person or remote, the privacy of 
the subject will be maintained. Consenting investigators (and participant/consent designee, when 
in person) will be located in a private area (e.g., clinic consult room). When consent is conducted 
remotely, the participant/consent designee will be informed of the private nature of the discussion 
and will be encouraged to relocate to a more private setting if needed. 
Consent will be documented with required signatures on the physical document (which includes 
the printout of an electronic document sent to participant) or as described below, with a manual 
(non-electronic) signature on the electronic document.   When required, witness signature will be 
obtained similarly as described for the investigator and participant.
Manual (Non-Electronic) Signature on Electronic Document:
When a manual signature on an electronic document is used for the documentation of consent 
at the NIH Clinical Center, this study will use the following to obtain the required signatures:

Adobe platform (which is not 21 CFR Part 11 compliant); or,  

iMedConsent platform (which is 21 CFR Part 11 compliant)
During the consent process, participants and investigators will view individual copies of the 
approved consent document on screens at their respective locations (if remote consent); the 
same screen may be used when in the same location, but is not required.  
Both the investigator and the participant will sign the document using a finger, stylus or mouse. 
Note: Refer to the CCR SOP PM-2, Obtaining and Documenting the Informed Consent Process 
for additional information (e.g., verification of participant identity when obtaining consent 
remotely) found here.
10.6.1 Consent Process for Adults Who Lack Capacity to Consent to Research Participation
For participants addressed in Section 10.3, an LAR will be identified consistent with Policy 403 
and informed consent obtained from the LAR, as described in Section 10.6.
10.6.2 Request for Waiver of Consent for Screening Activities
Prior to the subject signing the consent for this study pre-screening activities listed in Section 2.2.1 
may be performed. 
We request a waiver of consent for these activities as they involve only minimal risk to the subjects.  
A waiver will not adversely affect the rights and welfare of the subjects given that the activities 


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are only intended to determine suitability for screening for participation in research protocols.  
These activities could not practicably be carried out without the wavier as central recruiting 
services, utilized in the NIH Clinical Center, perform pre-screening activities for multiple studies 
and obtaining consent for each one is beyond their resources.  The subjects will be provided with 
additional pertinent information after participation as they will be informed whether or not they 
are eligible to sign a consent for additional screening.
11 REGULATORY AND OPERATIONAL CONSIDERATIONS 
11.1 STUDY DISCONTINUATION AND CLOSURE
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause. Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to study participants, 
investigator, the sponsor and regulatory authorities. If the study is prematurely terminated or 
suspended, the Principal Investigator (PI) will promptly inform study participants, the Institutional 
Review Board (IRB), and sponsor and will provide the reason(s) for the termination or suspension.  
Study participants will be contacted, as applicable, and be informed of changes to study visit 
schedule.
Circumstances that may warrant termination or suspension include, but are not limited to:

Determination of unexpected, significant, or unacceptable risk to participants

Demonstration of efficacy that would warrant stopping   

Insufficient compliance to protocol requirements

Data that are not sufficiently complete and/or evaluable

Determination that the primary endpoint has been met

Determination of futility
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the sponsor, and IRB as applicable.
11.2 QUALITY ASSURANCE AND QUALITY CONTROL
The site will perform internal quality management of study conduct, data and biological specimen 
collection, documentation and completion. An individualized quality management plan will be 
developed to describe a site’s quality management.
Quality control (QC) procedures will be implemented beginning with the data entry system and 
data QC checks that will be run on the database will be generated. Any missing data or data 
anomalies will be communicated to the site(s) for clarification/resolution.
Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical 
trial is conducted and data are generated and biological specimens are collected, documented 
(recorded), and reported in compliance with the protocol, International Conference on 
Harmonisation Good Clinical Practice (ICH GCP), and applicable regulatory requirements (e.g., 
Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)). 
The investigational site will provide direct access to all trial related sites, source data/documents, 
and reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and 
regulatory authorities.


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11.3 CONFLICT OF INTEREST POLICY
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons who have 
a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed and 
managed. Furthermore, persons who have a perceived conflict of interest will be required to have 
such conflicts managed in a way that is appropriate to their participation in the design and conduct 
of this trial. The study leadership in conjunction with the National Cancer Institute has established 
policies and procedures for all study group members to disclose all conflicts of interest and will 
establish a mechanism for the management of all reported dualities of interest.
11.4 CONFIDENTIALITY AND PRIVACY
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, and the sponsor(s). This confidentiality is extended to cover testing of biological 
samples and genetic tests in addition to the clinical information relating to participants. Therefore, 
the study protocol, documentation, data, and all other information generated will be held in strict 
confidence. No information concerning the study or the data will be released to any unauthorized 
third party without prior written approval of the sponsor. 
All research activities will be conducted in as private a setting as possible.
The study monitor, other authorized representatives of the sponsor, representatives of the 
Institutional Review Board (IRB), and/or regulatory agencies may inspect all documents and 
records required to be maintained by the investigator, including but not limited to, medical records 
(office, clinic, or hospital) and pharmacy records for the participants in this study. The clinical 
study site will permit access to such records.
The study participant’s contact information will be securely stored at the/each clinical site for 
internal use during the study. At the end of the study, all records will continue to be kept in a secure 
location for as long a period as dictated by the reviewing IRB, Institutional policies, or sponsor 
requirements.
Study participant research data, which is for purposes of statistical analysis and scientific reporting, 
will be stored at the NCI CCR. This will not include the participant’s contact or identifying 
information. Rather, individual participants and their research data will be identified by a unique 
study identification number. The study data entry and study management systems used by the 
clinical site(s) and by NCI CCR research staff will be secured and password protected. At the end 
of the study, all study databases will be archived at the NIH.
To further protect the privacy of study participants, a Certificate of Confidentiality has been issued 
by the National Institutes of Health (NIH). This certificate protects identifiable research 
information from forced disclosure. It allows the investigator and others who have access to 
research records to refuse to disclose identifying information on research participation in any civil, 
criminal, administrative, legislative, or other proceeding, whether at the federal, state, or local 
level. By protecting researchers and institutions from being compelled to disclose information that 
would identify research participants, Certificates of Confidentiality help achieve the research 
objectives and promote participation in studies by helping assure confidentiality and privacy to 
participants. 


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12 PHARMACEUTICAL INFORMATION  
Cisplatin, mitomycin C and sodium thiosulfate are being used off label for the investigation.  
However, the investigation is not intended to support a new indication for use or any other 
significant changes to labeling or advertising in any of the commercial agents used on the study. 
The investigation does not involve a route of administration or dosage level in use in a patient 
population or other factor that significantly increases the risks (or decreases the acceptability of 
the risks) associated with the use of the drug products, therefore an IND will not be submitted.
For this study, all drugs are commercially available, therefore, Investigator Brochures are not 
applicable to these drugs. Information about commercial drugs is publicly available in the package 
insert and other resources. Refer to the package inserts for complete information. 
12.1 CISPLATIN
12.1.1 Source 
Cisplatin is commercially available as a white lyophilized powder in 10cc and 50cc vials with 
mannitol and sodium chloride (Platinol, Bristol-Myers, Squibb, Princeton, NJ). It will be 
purchased from commercial sources by the NIH Clinical Center Pharmacy Department.
12.1.2 Toxicity 
Cisplatin produces renal tubular toxicities associated with renal insufficiency and electrolyte, (i.e. 
magnesium, potassium, calcium, phosphate, bicarbonate) wasting which may result in significant 
hypomagnesemia and hypokalemia. Neurotoxicity manifests as both sensory and motor peripheral 
neuropathies. Cisplatin is also toxic to the 8th cranial nerve producing ototoxicity which consists 
primarily of deficits in high frequency auditory acuity, but may include vestibular abnormalities. 
Systemic administration of cisplatin at doses similar to those planned in this study are associated 
with significant nausea and vomiting and bone marrow suppression, particularly leukopenia and 
thrombocytopenia. Transient moderate elevations of hepatic transaminases, (i.e. AST, ALT) and 
acute systemic allergic reactions including anaphylaxis may also occur. The prior Phase I study of 
CHPP with cisplatin has not identified any regional intraperitoneal toxicity from cisplatin. The 
dose limiting systemic toxicity was renal toxicity at doses of 350 mg/M2. No other systemic 
toxicities were identified at that dose level.   
12.1.3 Formulation and Preparation 
Vials containing 10 and 50 mg of cisplatin will be reconstituted with 10 and 50 cc water for 
injection, USP, respectively to a concentration of 1 mg/mL. The total dose of cisplatin will be 
injected into a bag of 0.9% sodium chloride for injection, USP, to make 1 liter of final volume (± 
10%) prior to administration.  
12.1.4 Stability and Storage 
After reconstitution with water for injection, USP, to a concentration of 1 mg/mL, cisplatin is 
stable at controlled room temperature (240C + 20C) at 370C, and at 600C for at least 14 days. 
Further dilution at 0.05 or 0.5 mg/mL with 0.9% sodium chloride injection (NS), USP, yields a 
solution that is stable for at least 24 hrs at room temperature. Intact vials in reconstituted solution 
should be maintained at room temperature.


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12.1.5 Administration Procedures
Cisplatin at a dose of 90 mg/m2 diluted in 1L of 1.5% dextrose dialysis solution will be added to 
a stable perfusion system at a flow rate of 1 L/min after draining an equivalent volume. If dialysis 
solution is not available, then 0.9% sodium chloride will be used. 
12.1.6 Incompatibilities  
 Refer to the package insert for complete information about this product.
12.2 MITOMYCIN 
12.2.1 Source
Mitomycin C is commercially available as a white lyophilized powder in 5mg, 20mg or 40mg vials 
with mannitol (Bedford Laboratories, OH). It will be purchased from commercial sources by the 
NIH Clinical Center Pharmacy Department.
12.2.2 Toxicity
Mitomycin is known to cause bone marrow suppression, notably thrombocytopenia and 
leukopenia which may contribute to infections in an already compromised patient.  Hemolytic 
Uremic Syndrome (HUS) a serious complication of chemotherapy has been reported in patients 
receiving systemic mitomycin. Other adverse reactions include integument and mucous membrane 
toxicity, renal toxicity and pulmonary toxicity
12.2.3 Formulation and Preparation
Each vial contains either mitomycin 5 mg and mannitol 10 mg, mitomycin 20 mg and mannitol 40 
mg, or mitomycin 40 mg and mannitol 80 mg. To administer, add Sterile Water for Injection, 10 
mL, 40 mL, or 80 mL respectively. Shake to dissolve. If product does not dissolve immediately, 
allow to stand at room temperature until solution is obtained.
12.2.4 Stability and Storage 
Unreconstituted mitomycin is stored at room temperature is stable for the lot life indicated on the 
package. Avoid excessive heat (over 40° C, 104° F).  Reconstituted with Sterile Water for Injection 
to a concentration of 0.5 mg per mL, mitomycin is stable for 14 days refrigerated or 7 days at room 
temperature. 
12.2.5 Administration Procedures
Mitomycin 10 mg/m2 diluted in sterile water will be added to the perfusion circuit via syringe or 
infusion bag and administered via circuit to the peritoneal cavity.
12.2.6 Incompatibilities
Refer to the package insert for complete information about this product
12.3 SODIUM THIOSULFATE
12.3.1 Source
The commercially available product will be purchased by the NIH Clinical Center Pharmacy 
Department. 


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12.3.2 Toxicity
Other than osmotic disturbances, sodium thiosulfate is well tolerated in humans. Large orally 
administered doses are associated with a cathartic effect. In preclinical studies in dogs continuous 
i.v. administration of sodium thiosulfate has produced hypovolemia presumably due to an osmotic 
diuretic effect.
There have been no controlled clinical trials conducted to systematically assess the adverse events 
profile of sodium thiosulfate. The medical literature has reported the following adverse events in 
association with sodium thiosulfate administration. These adverse events were not reported in the 
context of controlled trials or with consistent monitoring and reporting methodologies for adverse 
events. Therefore, frequency of occurrence of these adverse events cannot be assessed.

Cardiovascular system: hypotension

Central nervous system: headache, disorientation

Gastrointestinal system: nausea, vomiting

Hematological: prolonged bleeding time

Body as a whole: salty taste in mouth, warm sensation over body
In humans, rapid administration of concentrated solutions or solutions not freshly prepared, and 
administration of large doses of sodium thiosulfate have been associated with a higher incidence 
of nausea and vomiting. However, administration of 0.1 g sodium thiosulfate per pound up to a 
maximum of 15 g in a 10-15% solution over 10-15 minutes was associated with nausea and 
vomiting in 7 of 26 patients without concomitant cyanide intoxication.
In a series of 11 human subjects, a single intravenous infusion of 50 mL of 50% sodium thiosulfate 
was associated with increases in clotting time 1-3 days after administration. However, no 
significant changes were observed in other hematological parameters.
12.3.3 Formulation and Preparation
Sodium thiosulfate injection, USP, is commercially available as a sterile nonpyrogenic solution of 
sodium thiosulfate dissolved in water for injection, USP, at concentrations of 10% (100 mg/mL) 
at 25% (250 mg/mL). The commercial formulation may also contain boric acid and sodium 
hydroxide to adjust the pH to 8.5 - 9.0. 
12.3.4 Stability and Storage
Refer to the package insert for complete information about this product. 
12.3.5 Administration Procedures
Sodium thiosulfate will be administered will be administered by continuous intravenous infusion 
starting immediately prior to the perfusion and continuing for a total of 12 hours.
A loading dose of 7.5 gm/m2 of sodium thiosulfate will be diluted in 150cc of 0.9% sodium 
chloride for injection. This loading dose will be infused over 20 minutes beginning with the 
addition of cisplatin to the peritoneal perfusion circuit.


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Immediately following this bolus dose an additional 25.56 gm/m2 of sodium thiosulfate will be 
diluted in 1000cc of 0.9% sodium chloride for injection for a maintenance infusion of 2.13 gm/m2 
per hour for 12 hours. The maintenance infusion will be delivered by infusion pump.
12.3.6 Incompatibilities
Refer to the package insert for complete information about this product.


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Li H, Wang Z, Zhang W, Qian K, Xu W, Zhang S. Fbxw7 regulates tumor apoptosis, 
growth arrest and the epithelial-to-mesenchymal transition in part through the RhoA 
signaling pathway in gastric cancer. Cancer Lett. 2016;370(1):39-55.
62.
Cerami E, Gao J, Dogrusoz U, et al. The cBio cancer genomics portal: an open platform 
for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2(5):401-
404.
63.
Gao J, Aksoy BA, Dogrusoz U, et al. Integrative analysis of complex cancer genomics 
and clinical profiles using the cBioPortal. Sci Signal. 2013;6(269):pl1.
64.
Sugarbaker PH, Yu W, Yonemura Y. Gastrectomy, peritonectomy, and perioperative 
intraperitoneal chemotherapy: the evolution of treatment strategies for advanced gastric 
cancer. Semin Surg Oncol. 2003;21(4):233-248.
65.
Jacquet P, Sugarbaker PH. Clinical research methodologies in diagnosis and staging of 
patients with peritoneal carcinomatosis. Cancer Treat Res. 1996;82:359-374.
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Edge SB, Byrd DR, Compton CC, eds. AJCC cancer staging manual. 7th ed. New York: 
Springer-Verlag; 2009.
67.
Garland SN, Pelletier G, Lawe A, et al. Prospective evaluation of the reliability, validity, 
and minimally important difference of the functional assessment of cancer therapy-gastric 
(FACT-Ga) quality-of-life instrument. Cancer. 2011;117(6):1302-1312.


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Abbreviated Title: HIPEC for Gastric Cancer
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14 APPENDICES
14.1 APPENDIX A: PERFORMANCE STATUS CRITERIA
ECOG Performance Status Scale
Grade
Descriptions
0
Normal activity.  Fully active, able to carry on all 
pre-disease performance without restriction.
1
Symptoms, but ambulatory.  Restricted in physically 
strenuous activity, but ambulatory and able to carry 
out work of a light or sedentary nature (e.g., light 
housework, office work).
2
In bed <50% of the time.  Ambulatory and capable 
of all self-care, but unable to carry out any work 
activities.  Up and about more than 50% of waking 
hours.
3
In bed >50% of the time.  Capable of only limited 
self-care, confined to bed or chair more than 50% of 
waking hours.
4
100% bedridden.  Completely disabled.  Cannot 
carry on any self-care.  Totally confined to bed or 
chair.
5
Dead.


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Abbreviated Title: HIPEC for Gastric Cancer
Version Date: 12/28/2021
14.2 APPENDIX B: FACT-GA (VERSION 4)


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Abbreviated Title: HIPEC for Gastric Cancer
Version Date: 12/28/2021


52
Abbreviated Title: HIPEC for Gastric Cancer
Version Date: 12/28/2021


53
Abbreviated Title: HIPEC for Gastric Cancer
Version Date: 12/28/2021
14.3 APPENDIX C: CARCINOMATOSIS EXTENT EVALUATION


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Abbreviated Title: HIPEC for Gastric Cancer
Version Date: 12/28/2021
14.4 APPENDIX D: GENERAL SPECIMEN COLLECTION REFERENCE (REFER TO OFFICIAL 
TIMEPOINTS IN PROTOCOL 13C0176)
Note: This specimen collection appendix is solely for general reference only. Official specimen 
collection timepoints will be as indicated in protocol 13C0176. 
Venous research blood and urine samples will be collected at Pre-Op and Post-Op visits, 
approximately 1, 3, 6, 9, 12, 15, 18, 21 and 24 months from the date of operation, and then 
every 6 months during Years 3-5, and then yearly thereafter: 

8 mL blood in an EDTA lavender top tube; 

8 mL blood in a Streck cell free DNA tube; 

8 mL blood (plasma) in a Sodium Heparin green top tube; 

8 mL blood in a CPT blue/black top tube; 

8 mL blood (serum) in SST gold or marble top tube; 

45 mL spot urine sample in a urine clean catch container.  
Normal and tumor tissue will be collected for research during the clinically indicated surgical 
operation prior to HIPEC (see Section 3.4.2.1). These research tissue will be procured according 
to NIH Clinical Center standard of practice. Peritoneal lavage fluid will be sent for 
cytopathologic analysis for research purposes. 


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Abbreviated Title: HIPEC for Gastric Cancer
Version Date: 12/28/2021
15 TABLES AND FIGURES
15.1 TABLE 1: SYSTEMATIC REVIEW
Gastric Cancer 
Author, Year 
(Study Type)
Total/
(H)IPEC/
Other/
No HIPEC
Stage
I-III       IV
IP 
Method
IP Agent & dose
Systemic Tx
Median 
Follow-
up
Clinical Outcome
P-Value
Kang et al., 2013
(RCT)
521
258
263
217
214
46
44
NIPEC
Sx & SC 
CDDP 100mg in 1L x 2hr
NIPEC: IV MMC, PO 
DFU, IV CDDP 
Sx: IV MMC, po 
DFU, MMC
80.1mo
75.6mo
3yr OS 71% vs 60%
5yr OS: 59% vs 50%
0.006
Miyashiro et al., 
2011
(RCT)
268
135
133
135
131
0
2
NIPEC
Sx & SC
CDDP 70mg/m2 x2h
IV CDDP 70mg/m2 
d14, 5FU 700mg/m2 
qd d14-16, po UFT qd 
4wk-12mo
6yr
5yr OS 62.0% NIPEC vs 60.9% 
Sx alone
5yr DFS 57.5% vs 55.6% 
0.482
Yonemura et al., 
2001
(RCT)
139
48
44
47
35
29
38
13
15
9
HIPEC
NIPEC
Sx alone
HIPEC: MMC 30mg, 
CDDP 300mg
NIPEC: Same at 37C
n/a
ND
5.5yr
5yr OS: 61% HIPEC vs 44% 
NIPEC or 42% Sx alone 
0.021
Fujimoto et al., 
1999
(RCT)
141
71
70
58
62
13
8
HIPEC
Sx & SC
MMC 10ug/mL in 3-4L
Chemo NOS
ND
2yr OS: 88% HIPEC vs 77% Sx 
alone
4yr OS: 76% vs 58%
8yr OS: 62% vs 49%
0.0362
Shimoyama et al., 
1999 (RCT)
87
30
24
33
30
23
32
1
1
1
NIPEC 
Portal 
Sx & SC
NIPEC: MMC 10mg 
PV: Same
All: IV CDDP & UFT
47mo
1yr OS: 81% (Diffuse type 
control), vs 94% (Diffuse type 
NIPEC)
4yr OS: 32%, vs. 73%
0.049
Rosen et al., 1998
(RCT)
91
46
45
91
0
NIPEC
Sx alone
MMC 50mg, CH 375mg 
x 24hr
ND
597d
Median OS 738.9d NIPEC vs. 
515.4d Sx 
DFS 554.8d vs 380.4d 
0.44
0.48
Yu et al., 1998
(RCT)
248
125
123
89
88
36
35
EPIC
Sx alone
EPIC: MMC 10mg/m2 
POD1, 5FU 700mg/m2 in 
1L qd x4 starting POD2
ND
36mo
5yr OS of EPIC 54% vs 38%
0.0278
Ikeguchi et al., 
1995
(RCT)
174
78
64
14
HIPEC 
MMC 80-100 mg/m2
IV MMC 10mg on 
d7&14, po UFT 
600mg/d d14-6mo
6yr
5yr OS 51% HIPEC vs 46% Sx 
alone
NS


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Abbreviated Title: HIPEC for Gastric Cancer
Version Date: 12/28/2021
96
76
20
Sx & SC
Same MMC on 
d0,7&14, same UFT
Takahashi et al., 
1995
(RCT)
113
56
57
ND
ND
NIPEC
Sx alone
MMC 50mg in 100mL & 
CH 375mg x3hr
ND
ND
2yr OS: 66% NIPEC vs 35% 
control
3yr OS: 66% vs 20%
<0.01
Fujimura et al., 
1994
(RCT)
58
22
18
18
17
13
10
5
5
8
HIPEC 
NIPEC 
Sx alone
HIPEC: CDDP 300 mg, 
MMC
NIPEC: same at 37-38C
ND
35mo
37mo
31mo
1yr OS: 95% HIPEC, 81% 
NIPEC, 43% Sx alone
2yr OS: 89%, 75%, 23%
3yr OS: 68%, 51%, 23% 
<0.01
Hamazoe et al., 
1994
(RCT)
82
42
40
38
33
4
7
HIPEC 
Sx alone
MMC 10ug/mL
ND
ND
5yr OS 64.3%
HIPEC vs. 52.5%
Median OS: 77mo vs 66mos
0.2427
Sautner et al., 
1994
(RCT)
67
33
34
26
27
7
7
EPIC
Sx alone
POD 10-28: CDDP 90 
mg/m2 q1mo
ND
72.5mo
Median OS 17.3 vs. 16.0 mo
OS: 1yr - 66.8% vs 57.6%, 3yr - 
33.3% vs 30.3%; 5 yr - 21.2% vs 
23.6%
0.8
0.6
Kaibara et al., 
1989
(RCT)
82
42
40
42
40
0
0
HIPEC
Sx alone
MMC 10mg/L
ND
ND
5yr OS 71.5%  HIPEC vs 59.7% 
Sx alone
NS
Koga et al., 1988
(RCT)
60
32
28
30
24
2
4
HIPEC
Sx alone
MMC 8-10 mg/L in 2L
ND
ND
30mo OS: 83% HIPEC vs 67.3% 
Sx alone
NS
Topuz et al., 2002
(PSA)
39
39
0
EPIC
Post-op 3-6wk: CDDP 60 
mg/m2, MMC 12 mg/m2, 
5FU 600 mg/m2, FA 60 
mg/m2 q4wk x 6
ND
23mo
Median DFS 12mo & median OS 
19 mo Cumulative 5-yr DFS & 
OS were 24.7% & 30.7% 
n/a
Jones et al., 1994
(PSA)
18
16
2
EPIC
Median 6wk post-op: 
CDDP 60mg/m2 q21d x4 
(x6 if peritoneal washings 
positive)
ND
ND
Median OS 17 mo
ND
Atiq et al., 1993
(PSA)
35
34
1
EPIC
Post-op14-28d: CDDP 25 
mg/m2 & FU 750 mg qd 
x 4; q28d  x 5                       
FU IV750 mg/m2 x4d
24mo
Median OS 24.9 mo
n/a
Hirose et al., 1999
(PSA/CC)
55
15
40
12
33
3
7
HIPEC
Sx & SC
CDDP 100mg, MMC 
20mg, Etoposide 100mg 
2-3wk post: IV MMC 
6mg/m2, 5FU 
375mg/m2 qwk x 3
14.6mo
3yr OS: 48.9% HIPEC vs 28.8% 
Sx 
5yr OS: 39.1% vs 17.3%
0.0142 
0.0425 


57
Abbreviated Title: HIPEC for Gastric Cancer
Version Date: 12/28/2021
Abbreviations:   HIPEC, heated intraperitoneal chemotherapy; Tx, treatment; RCT, randomized control trial; Sx, surgery; MMC, mitomycin-C; CDDP, cisplatin; op, 
operative; ND, not discussed; OS, overall survival; SC, systemic chemotherapy; IV, intravenous; d, day; UFT, 1-(2-tetrahydrofuryl)-5-fluorouracil/uracil (1:4); NS, non-
significant; PSA, prospective single arm; FA, folinic acid; DFS, disease free survival; NOS, not otherwise specified; EPIC, early post-operative intraperitoneal 
chemotherapy; POD, post-operative day; MMC-CH, mitomycin-C bound to activated carbon particles); DFU, po doxifluridine; CC, case control.


58
Abbreviated Title: HIPEC for Gastric Cancer
Version Date: 12/28/2021
15.2 TABLE 2: CYTOPATHOLOGIC ANALYSIS DEFINITIONS
Results
Description
Negative
No evidence of cancerous cells
Malignant (Positive)
Morphologic evidence of cancerous cells
Atypical cells of undetermined 
significance
Indistinguishable morphologic cellular changes;
(Requires repeat cytologic sampling before protocol 
eligibility can be determined.)
Non-diagnostic
Not enough cellular material or poor cell 
preservation
Not satisfactory
Not enough cellular material or poor cell 
preservation
Peritoneal lavage fluid undergoes cytospin and papanicolaou or diff-quik stain for morphologic analysis. 
Remaining cell block will undergo formalin fixation and paraffin embedding for H&E staining, and 
immunohistochemistry using an antibody panel of cytokeratin, BerEP4, B72.3 and claudin-4.


59
Abbreviated Title: HIPEC for Gastric Cancer
Version Date: 12/28/2021
15.3 FIGURE 1: OVERALL SURVIVAL OF PATIENTS WITH POSITIVE CYTOLOGY ONLY COMPARED TO 
VISIBLE METASTATIC DISEASE AT TIME OF LAPAROSCOPY


60
Abbreviated Title: HIPEC for Gastric Cancer
Version Date: 12/28/2021
15.4 FIGURE 2: RANDOM EFFECT MODEL INDICATING POTENTIAL SURVIVAL ADVANTAGE OF IP CHEMO 
IN SYSTEMATIC LITERATURE REVIEW
 
     Favors Adjuvant IP Chemo      Favors No IP Chemo


61
Abbreviated Title: HIPEC for Gastric Cancer
Version Date: 12/28/2021
15.5 FIGURE 3: ONCOPRINT INDICATING RECURRING GENOMIC ALTERATIONS IN MULTIPLE GASTRIC 
ADENOCARCINOMA SUBTYPES

ICF_001.pdf: 
PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 01/12/2022
Page 1 of 15
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
PRINCIPAL INVESTIGATOR:
Jeremy L. Davis, MD
STUDY TITLE: 
Phase II Trial of Heated Intraperitoneal Chemotherapy 
and Gastrectomy for Gastric Cancer with Positive 
Peritoneal Cytology
STUDY SITE:  
NIH Clinical Center
Cohort: 
Standard
 
Consent Version: 
01/12/2022
 
WHO DO YOU CONTACT ABOUT THIS STUDY? 
Jeremy L. Davis, MD, by phone at 240-858-3731 or email at jeremy.davis@nih.gov 
This consent form describes a research study and is designed to help you decide if you would like 
to be a part of the research study.  
You are being asked to take part in a research study at the National Institutes of Health (NIH). 
Members of the study team will talk with you about the information described in this document. 
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). Take the time needed 
to ask any questions and discuss this study with NIH staff, and with your family, friends, and 
personal health care providers. Taking part in research at the NIH is your choice.
If the individual being asked to participate in this research study is not able to give consent to be 
in this study, you are being asked to give permission for this person as their decision-maker. The 
term “you” refers to you as the decision-maker and/or the individual being asked to participate in 
this research, throughout the remainder of this document. 
IT IS YOUR CHOICE TO TAKE PART IN THE STUDY
You may choose not to take part in this study for any reason. If you join this study, you may change 
your mind and stop participating in the study at any time and for any reason. In either case, you 
will not lose any benefits to which you are otherwise entitled. However, to be seen at the NIH, you 
must be taking part in a study or are being considered for a study. If you do choose to leave the 
study, please inform your study team to ensure a safe withdrawal from the research.  
WHY IS THIS STUDY BEING DONE?
Gastric cancer is the third most common type of cancer; few patients diagnosed with this disease 
live beyond 5 years after being diagnosed. The standard treatment for gastric cancer is a 
combination of chemotherapy drugs. At the NIH Clinical Center, we have treated patients with 
other types of cancer including gastric cancer, cancer of the appendix, and other gastrointestinal 
cancers whose tumors have spread throughout their abdomen with aggressive surgical removal of 
their tumors followed by heated chemotherapy called HIPEC (heated intraperitoneal peritoneal 
IRB NUMBER: 17C0070
IRB APPROVAL DATE: 01/19/2022


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 01/12/2022
Page 2 of 15
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
chemotherapy) with good results. Cisplatin and mitomycin-C, the chemotherapy drugs used on 
this study are approved by the FDA for cancers other than gastric cancers; however, there is strong 
evidence that they are effective in the treatment of gastric cancers. We think that this type of 
treatment may help patients with gastric cancers.  In this study, we would like to determine if 
surgical removal of the gastric cancer plus heated chemotherapy can improve survival in patients 
with gastric cancers. 
WHY ARE YOU BEING ASKED TO TAKE PART IN THIS STUDY?
You are being asked to take part in this study because you have been diagnosed with gastric cancer 
and although your tumor has spread throughout your abdomen, we think that we will be able to 
remove some or potentially most of the tumors with an operation. Standard chemotherapy usually 
does not prevent tumors like yours from growing following surgery, but we think that giving heated 
chemotherapy directly into your abdomen may prevent or increase the length of time that it takes 
for the tumors to grow back.
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
Up to 40 people will take part in this study.
DESCRIPTION OF RESEARCH STUDY
Stage
Timeframe
Location
Events
Evaluations 
before you 
receive any 
study therapy
1-8 weeks
Inpatient and out 
patient  
Evaluation of your medical records, 
scans, and/or tissue from previous 
surgeries you may have had to 
determine if you are eligible for this 
study, other medically indicated tests 
as needed, CT or PET/CT, and 
completion of Quality of Life 
research questionnaire
Surgery, 
HIPEC and 
recovery  
4-12 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 your tumors. 
During this time routine post-op care 
such will be done if your doctor 
thinks you need them 
Follow up
At 1 and 3 months after 
your surgery, then every 3 
months until 2 years after 
your surgery, then every 6 
months for 3 years, then 
every year thereafter
NIH Clinical 
Center as 
possible
Physician visits for medical follow 
up examinations, to include 
medically indicated tests as needed, 
CT or PET/CT (starting at 3 months 
post-surgery), and completion of 
Quality of Life research 
questionnaire (for the first 2 years 
only)
IRB NUMBER: 17C0070
IRB APPROVAL DATE: 01/19/2022


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 01/12/2022
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
WHAT WILL HAPPEN IF YOU TAKE PART IN THIS RESEARCH STUDY?  
Before you begin the study
You will have several tests performed in order to determine whether you meet the criteria to 
participate in this study and to be certain it is safe for you to have the operation and the HIPEC. 
We will ask you questions about your medical history and may ask about the medical history of 
your family members. We will ask to review your medical records, and will perform a physical 
exam, EKG, routine blood tests (a few tablespoons), and a CT or PET/CT scan to examine your 
chest, abdomen, pelvis. (Your study doctor will let you know if you need MRI scans instead.) 
We will also request a tissue sample from your tumor if it is available from a previous surgery to 
confirm your diagnosis. 
A pregnancy test (urine or blood sample) will also be performed if you are a female who is 
capable of having children.  
You will also be asked to co-enroll on the Surgical Oncology Program’s tissue collection protocol 
13C0176 (“Tumor, Normal Tissue and Specimens from Patients Undergoing Evaluation or 
Surgical Resection of Solid Tumors”) so that any remaining tumor samples from your surgery and 
the blood or urine collected as a part of this study can be used for future research purposes. Usually, 
when cancer tissue is removed, very small amounts of nearby normal tissue are also removed. If 
there is normal tissue left over from the removal of your cancer during surgery, we would also like 
to receive some of this tissue for research. The surgical removal of your visible cancer tumors is 
not part of this research study and will only be done to treat your disease.
During this study we may collect information from your medical records including your age, 
diagnosis, disease history, clinical lab and imaging results, medical treatments, and response to 
treatments for research purposes. 
You will be removed from the study if you are found to be not eligible.
During the study
If you are eligible for the study and agree to participate, you will be asked for a CT or PET/CT 
scan to measure your disease pre-treatment for our research. You will be asked to complete a 
Quality of Life questionnaire assessing your general well-being and function for research purposes 
during your pre-treatment evaluation. It will take about 30 minutes to complete and will only be 
done if you can complete the survey in English. 
If you are a female who is capable of having children, a pregnancy test (blood sample) will be 
performed prior to your surgery.
Surgery
Once you have completed all the testing and your physician has reviewed the results to determine 
that this procedure is safe for you, you will be admitted to the hospital.  Most patients are admitted 
1-2 days before their operation.  Your physician will explain the surgical procedure and HIPEC 
and will answer any questions you may have.  You will be asked to sign a separate consent for the 
operation. 
IRB NUMBER: 17C0070
IRB APPROVAL DATE: 01/19/2022


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 01/12/2022
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
You will undergo a major surgical operation to remove as many of your visible cancer tumors as 
possible.  At the end of the surgical procedure, while still in the OR (and under general anesthesia) 
you will receive HIPEC cisplatin and mitomycin C. Following the procedure, you will likely 
remain in the hospital for 7-21 days and will then be seen in clinic at one month and then at 3-
months post-surgery until fully recovered. 
If your surgeon cannot remove the majority of your tumors or if the surgeon considers it unsafe, 
you will not receive the HIPEC.
HIPEC
Two catheters (or thin tubes) will be put in your abdomen.  The cisplatin and mitomycin C will be 
given to you through one catheter in your abdomen and drained out through another, bathing the 
inside of your abdomen with cisplatin.  This chemotherapy solution will be washed through your 
abdomen over 60 minutes at a temperature a few degrees above your normal body temperature.  
After your abdomen has been bathed for 60 minutes, the chemotherapy will be rinsed out and the 
catheters will be removed.  During this procedure, we will carefully monitor your temperature. If 
your body temperature goes up during the procedure, we will use cooling blankets and ice packs 
to keep your body temperature normal.
In order to reduce the risk of side effects (especially kidney damage), from any of the cisplatin that 
may leak into your bloodstream while it is in your abdomen, a third medicine called sodium 
thiosulfate will be given to you through your vein during the HIPEC treatment.  Sodium thiosulfate 
binds to cisplatin in the blood and makes it less harmful.
Recovery 
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 
5-7 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.   
Follow Up
You will be asked to return to the NIH Clinical Center for follow up examinations after a month 
and then examinations and CT or PET/CT scan about every 3 months for the first 2 years, every 6 
months for the next 3 years, and then every year after that. 
If you are not able to come to the NIH Clinical Center for your follow up visit, we will contact you 
by phone, videocall or other NIH approved remote platforms, or e-mail and may ask that you send 
copies of your scans, lab works and physician notes to us. 
In certain cases, such as if your disease worsens after this therapy, we may ask that your follow up 
examinations start being every year (1 visit each year) earlier than indicated above.
IRB NUMBER: 17C0070
IRB APPROVAL DATE: 01/19/2022


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 01/12/2022
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
We will also ask you to complete the Quality of Life questionnaire during your follow up 
examinations, about every 3 months for the first 2 years.  It will take about 30 minutes to complete 
and will only be done if you can complete the survey in English.
BIRTH CONTROL
If you are a woman who is breast feeding or pregnant, you may not take part in the study because 
some of the medications used in this study may harm 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 two effective forms of birth control before starting study treatment, during study treatment 
(HIPEC and gastrectomy).  If you think that you or your partner is pregnant, you should tell your 
study doctor or nurse at once.  
Effective forms of birth control include: 
•
abstinence 

intrauterine device (IUD)
•
hormonal [birth control pills, injections, or implants]
•
tubal ligation
•
vasectomy
RISKS OR DISCOMFORTS OF PARTICIPATION
Surgery Risks
The operation to remove the tumors throughout your abdomen is likely to be quite extensive and 
will include HIPEC as well. The risks from these operations, HIPEC and general anesthesia 
include: 
Likely side effects:

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.

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 side effects:

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 HIPEC, 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.   
IRB NUMBER: 17C0070
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
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.  

Breathing problems which may require oxygen or rarely reinsertion of the breathing tube 
and breathing machine for a few days.

Slow and complicated wound healing which may require additional procedures and 
hospitalization.  
Rare but Serious side effects:

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.
Medication Risks
Cisplatin
COMMON, SOME MAY BE SERIOUS
In 100 people receiving Cisplatin, more than 20 and up to 100 may have:
Nausea, vomiting, 
Infection, especially when white blood cell count is low
Anemia which may cause tiredness, or may require blood transfusions
Bruising, bleeding
Kidney damage which may cause swelling, may require dialysis
Hearing loss including ringing in ears
OCCASIONAL, SOME MAY BE SERIOUS
In 100 people receiving Cisplatin, from 4 to 20 may have:
Hair loss
Change in taste
Diarrhea 
Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of 
breath, swelling of the face or throat
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OCCASIONAL, SOME MAY BE SERIOUS
In 100 people receiving Cisplatin, from 4 to 20 may have:
Confusion
Difficulty with balance
Numbness and tingling of the arms and legs
Blurred vision or changes in ability to see colors (especially blue or yellow)
RARE, AND SERIOUS
In 100 people receiving Cisplatin, 3 or fewer may have:
Cancer of bone marrow caused by chemotherapy later in life
Seizure
Mitomycin
COMMON, SOME MAY BE SERIOUS
In 100 people receiving Mitomycin, more than 20 and up to 100 may have:
Infection, particularly when white blood cell counts are low
Anemia which might require blood transfusion
Bruising, bleeding
Tiredness
Swelling of the body
Difficult, painful or frequent urination (when the drug is administered into the bladder)
Blood clot
OCCASIONAL, SOME MAY BE SERIOUS
In 100 people receiving Mitomycin, from 4 to 20 may have:
Loss of appetite
Nausea, vomiting
Sores in the mouth
Rash
Hair loss
Loss of fertility
Swelling and redness at the site of the medication injection
Fever
Anemia, kidney problems which may cause tiredness, bruising, swelling, or may require 
dialysis
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RARE, AND SERIOUS
In 100 people receiving Mitomycin, 3 or fewer may have:
Shortness of breath, cough, scarring of the lungs
Kidney failure that could require treatment with dialysis
Sodium thiosulfate
The medical literature has reported the following adverse events in association with sodium 
thiosulfate administration. 

Cardiovascular system: hypotension

Central nervous system: headache, disorientation

Gastrointestinal system: nausea, vomiting

Hematological: prolonged bleeding time

Body as a Whole: salty taste in mouth, warm sensation over body
Research Procedure Risks
Blood Draw
There is the risk of slight pain, bruising or infection when your blood is drawn.  Drawing blood 
may cause some people to faint.
Urine Collection
There are no physical risks associated with urine collection. 
Questionnaire 
The questionnaire may contain questions that are sensitive in nature. You are asked to only answer 
questions that you are comfortable with.
Electrocardiogram (EKG)
Some skin irritation can occur where the ECG electrodes are placed. Once the electrodes are placed 
and the test has begun, it is completely painless, and generally takes less than a minute to perform.  
After the test, the electrodes are removed.
Tumor Biopsy 
The likely side effects include discomfort or pain, redness, swelling, and/or bruising at the site of 
the needle insertion. Bleeding from the site of the needle insertion is a less likely risk. Rarely, 
significant infection or bleeding from this procedure, allergic reaction to the anesthetic, or 
formation of a scar at the site of needle entry occurs. If you will have sedation with the procedure, 
these risks will be discussed with you prior to the procedure. You will be asked to sign a separate 
consent form prior to any biopsy procedure. 
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Scans and Contrast 
CT, PET/CT and MRI scans are common standard imaging tests used in the diagnosis of cancer. 
The most common discomfort is the length of time a patient must lay still during a scan. 
Occasionally, a patient may become uncomfortable with the closed space of the machines, 
particularly the MRI. If this occurs, your doctor can order a medicine to help you relax during this 
scan. If a contrast agent (the special dye) is given with the scan there is a small risk of having a 
reaction to the contrast. In that small group of patients who have a reaction, the most common 
symptoms are nausea, pain in the vein where the contrast was given, a metallic or bitter taste in 
the mouth, and a warm or flushing feeling that lasts from 1-3 minutes. Rarely do these symptoms 
require any treatment. In very rare cases, people have had severe reactions that affect their 
breathing and heart rhythm. If you have had a reaction in the past, be sure to tell you doctor or 
nurse about it. 
An IV line may need to be inserted for administration of the contrast agent or anesthetic.  This can 
cause pain at the site where the IV is placed and carries a small risk of bruising or infection.
Patients with a cardiac pacemaker, neural pacemaker, some types of surgical clips, cochlear 
implants, foreign metal objects, permanent retainers, or any iron-containing material within the 
body should not undergo MRI, because of the effect of the strong magnet on these objects.
Risks of gadolinium during MRI:
Mild symptoms from gadolinium infusion occur in fewer than 1% of those who receive it and 
usually go away quickly.  Mild symptoms may include coldness in the arm during the injection, a 
metallic taste, headache, and nausea.  In an extremely small number, fewer than one in 300,000 
people, more severe symptoms have been reported including shortness of breath, wheezing, hives, 
and lowering of blood pressure. You should not receive gadolinium if you previously had an 
allergic reaction to it.  You will be asked about such allergic reactions before gadolinium is given.   
People with kidney disease are at risk for a serious reaction to gadolinium contrast called 
“nephrogenic systemic fibrosis” which has resulted in a very small number of deaths.  A blood test 
of your kidney function may be done within the month before an MRI scan with gadolinium 
contrast. You will not receive gadolinium for a research MRI scan if your kidney function is not 
normal or if you received gadolinium within the previous month. 
Most of the gadolinium contrast leaves the body in the urine. However, the FDA recently issued a 
safety alert that indicates small amounts of gadolinium may remain in the body for months to 
years. The effects of the retained gadolinium are not clear. At this time, retained gadolinium has 
not been linked to health risks in people whose kidneys work well. Some types of gadolinium 
contrast drugs are less likely to remain than others. In this study, we will use the gadolinium 
contrast drugs that are less likely to remain, whenever possible. We will also give you additional 
information called a “Medication Guide.” Upon request, we will give you individual information 
about retained gadolinium we see on your studies. 
What are the risks of radiation from being in the study?
During your participation in this research study, you may be exposed to radiation from up to 6 CT 
or PET/CT scans, as well as a potential CT-guided biopsy, during your first year on study.  The 
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amount of radiation exposure from these procedures is equal to approximately 8.0 rem. A rem is a 
unit of absorbed radiation. 
Every day, people are exposed to low levels of radiation that come from the sun and the 
environment around them.  The average person in the United States receives a radiation exposure 
of 0.3 rem per year from these sources.  This type of radiation is called “background radiation.”  
This study will expose you to more radiation than you get from everyday background radiation. 
No one knows for sure whether exposure to these low amounts of radiation is harmful to your 
body. 
The CT or PET/CT scans that you get in this study will expose you to roughly the same amount of 
radiation as 26.7 years’ worth of background radiation. Being exposed to too much radiation can 
cause harmful side effects such as an increase in the risk of cancer.  The risk depends on how much 
radiation you are exposed to. Please be aware that about 40 out of 100 people (40%) will get cancer 
during their lifetime, and 20 out of 100 (20%) will die from cancer. The risk of getting cancer from 
the radiation exposure in this study is 0.8 out of 100 (0.8%) and of getting a fatal cancer is 0.4 out 
of 100 (0.4%).
You may not participate in this study if you are pregnant. If you are able to become pregnant, we 
will perform a pregnancy test before exposing you to radiation. You must tell us if you may have 
become pregnant within the previous 14 days because the pregnancy test is unreliable during that 
time.
POTENTIAL BENEFITS OF PARTICIPATION
Are there benefits to taking part in this study? 
The aim of this study is to see if this experimental treatment will make persons with your disease 
live longer.  We do not know if you will receive personal, medical benefit from taking part in this 
study. These potential benefits could include shrinking of your tumor or lessening of your 
symptoms, such as pain, that are caused by the cancer.  Because there is not much information 
about the treatment’s effect on your cancer, 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.  
ALTERNATIVE APPROACHES OR TREATMENTS
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 treatment or care for your cancer without being in a study.

Taking part in another 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.
Please talk to your doctor about these and other options.
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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 gets worse during treatment 

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.
If you decide at any time to withdraw your consent to participate in the trial, we will not collect 
any additional medical information about you. If you withdraw your consent and leave the trial, 
any samples of yours that have been obtained for the study and stored at the NCI can be destroyed 
upon request. However, any samples and data generated from the samples that have already been 
distributed to other researchers or placed in the research databases cannot be recalled and 
destroyed.
CONFLICT OF INTEREST
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest.  This process is detailed in a COI Guide.  You may ask your research team for a copy 
of the COI 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.
No NIH investigator involved in this study receives payments or other benefits from any company 
whose drug, product or device is being tested. 
USE OF SPECIMENS AND DATA FOR FUTURE RESEARCH
Your samples will be stored for future use under the separate specimen collection protocol 
(13C0176) in which you have agreed to be co-enrolled.
However, to advance science, it is helpful for researchers to share information they get from 
studying human data.  They do this by putting it into one or more scientific databases, where it is 
stored along with information from other studies. A researcher who wants to study the information 
must apply to the database and be approved.  Researchers use data stored in scientific databases to 
advance science and learn about health and disease.  
We plan to keep some of your data that we collect on this study and use them for future research 
and share them with other researchers. We will not contact you to ask about each of these future 
uses.  These data will be stripped of identifiers such as name, address or account number, so that 
they may be used for future research on any topic and shared broadly for research purposes. Your 
data will be used for research purposes only and will not benefit you. It is also possible that the 
stored data may never be used.  Results of research done on your data will not be available to you 
or your doctor.  It might help people who have cancer and other diseases in the future.  
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In addition to the use and sharing of your data described above, we might remove any information 
from your data that can identify you such as name, address, or medical record number, and then 
use the data for additional research studies at the NIH or other places. If we do this, we might not 
contact you to ask your permission or otherwise inform you.
If you do not want your stored data used for future research, please contact us in writing and let us 
know that you do not want us to use your data.  Then your data will not be used for future research. 
However, it may not be possible to withdraw or delete data once they have been shared with other 
researchers.
COMPENSATION, REIMBURSEMENT, AND PAYMENT
Will you receive compensation for participation in the study?
Some NIH Clinical Center studies offer compensation for participation in research. The amount 
of compensation, if any, is guided by NIH policies and guidelines.
You will not receive compensation for participation in this study. 
Will you receive reimbursement or direct payment by NIH as part of your participation?
Some NIH Clinical Center studies offer reimbursement or payment for travel, lodging or meals 
while participating in the research. The amount, if any, is guided by NIH policies and guidelines.
On this study, the NCI will cover the cost for some of your expenses.  Some of these costs may 
be paid directly by the NIH and some may be reimbursed after you have paid.  Someone will 
work with you to provide more information. 
Will taking part in this research study cost you anything? 
NIH does not bill health insurance companies or participants for any research or related clinical 
care that you receive at the NIH Clinical Center. 

If some tests and procedures are performed outside the NIH Clinical Center, you may have 
to pay for these costs if they are not covered by your insurance company.

Medicines that are not part of the study treatment will not be provided or paid for by the 
NIH Clinical Center.

Once you have completed taking part in the study, medical care will no longer be provided 
by the NIH Clinical Center.
CLINICAL TRIAL REGISTRATION AND RESULTS REPORTING 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time.
CONFIDENTIALITY PROTECTIONS PROVIDED IN THIS STUDY  
Will your medical information be kept private? 
We will do our best to make sure that the personal information in your medical record will be kept 
private.  However, we cannot guarantee total privacy.  Organizations that may look at and/or copy 
your medical records for research, quality assurance, and data analysis include:
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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY

The NIH and other government agencies, like the Food and Drug Administration (FDA), 
which are involved in keeping research safe for people.

National Institutes of Health Intramural Institutional Review Board
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.
If we share your specimens or data with other researchers, in most circumstances we will remove 
your identifiers before sharing your specimens or data. You should be aware that there is a slight 
possibility that someone could figure out the information is about you. 
Further, the information collected for this study is protected by NIH under a Certificate of 
Confidentiality and the Privacy Act. 
Certificate of Confidentiality
To help us protect your privacy, the NIH Intramural Program has received a Certificate of 
Confidentiality (Certificate). With this certificate, researchers may not release or use data or 
information about you except in certain circumstances.  
NIH researchers must not share information that may identify you in any federal, state, or local 
civil, criminal, administrative, legislative, or other proceedings, for example, if requested by a 
court.  
The Certificate does not protect your information when it:  
1. is disclosed to people connected with the research, for example, information may be used 
for auditing or program evaluation internally by the NIH; or 
2. is required to be disclosed by Federal, State, or local laws, for example, when information 
must be disclosed to meet the legal requirements of the federal Food and Drug 
Administration (FDA); 
3. is for other research;
4. is disclosed with your consent. 
The Certificate does not prevent you from voluntarily releasing information about yourself or your 
involvement in this research. 
The Certificate will not be used to prevent disclosure to state or local authorities of harm to self or 
others including, for example, child abuse and neglect, and by signing below you consent to those 
disclosures. Other permissions for release may be made by signing NIH forms, such as the Notice 
and Acknowledgement of Information Practices consent.
Privacy Act
The Federal Privacy Act generally protects the confidentiality of your NIH medical records we 
collect under the authority of the Public Health Service Act.  In some cases, the Privacy Act 
protections differ from the Certificate of Confidentiality.  For example, sometimes the Privacy Act 
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MEDICAL RECORD
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allows release of information from your medical record without your permission, for example, if 
it is requested by Congress. Information may also be released for certain research purposes with 
due consideration and protection, to those engaged by the agency for research purposes, to certain 
federal and state agencies, for HIV partner notification, for infectious disease or abuse or neglect 
reporting, to tumor registries, for quality assessment and medical audits, or when the NIH is 
involved in a lawsuit.  However, NIH will only release information from your medical record if it 
is permitted by both the Certificate of Confidentiality and the Privacy Act.
POLICY REGARDING RESEARCH-RELATED INJURIES  
The NIH 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 NIH, the NIH Clinical Center, or the Federal 
Government. However, you have the right to pursue legal remedy if you believe that your injury 
justifies such action.
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, Dr. Jeremy 
Davis, MD, jeremy.davis@nih.gov, 240-858-3731. You may also call the NIH Clinical Center 
Patient Representative at 301-496-2626, or the NIH Office of IRB Operations at 301-402-3713, if 
you have a research-related complaint or concern.
CONSENT DOCUMENT 
Please keep a copy of this document in case you want to read it again.
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Adult Research Participant: I have read the explanation about this study and have been given the opportunity 
to discuss it and to ask questions. I consent to participate in this study.
Signature of Research Participant
Print Name of Research Participant
Date
Legally Authorized Representative (LAR) for an Adult Unable to Consent: I have read the explanation 
about this study and have been given the opportunity to discuss it and to ask questions. I am legally authorized 
to make research decisions on behalf of the adult participant unable to consent and have the authority to provide 
consent to this study. As applicable, the information in the above consent was described to the adult participant 
unable to consent who agrees to participate in the study.
Signature of LAR
Print Name of LAR
Date
Investigator:
Signature of Investigator
Print Name of Investigator
Date
Witness should sign below if either: 
1. A short form consent process has been used to enroll a non-English speaking subject or
2. An oral presentation of the full consent has been used to enroll a blind or illiterate subject
Witness:
Signature of Witness*
Print Name of Witness
Date
*NIH ADMINISTRATIVE SECTION TO BE COMPLETED REGARDING THE USE OF AN 
INTERPRETER:
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated
the administration of informed consent and served as a witness. The investigator obtaining consent may not 
also serve as the witness.
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated
the administration of informed consent but did not serve as a witness. The name or ID code of the person 
providing interpretive support is:
.
IRB NUMBER: 17C0070
IRB APPROVAL DATE: 01/19/2022