Clinical trial NCT01833832
Conditions: Adrenocortical Carcinoma Peritoneal Carcinomatosis
Keywords: Synergy for Cisplatin and Hyperthermia Rare Tumor Poor Prognosis
Sponsor: National Cancer Institute (NCI)
Start date: 2013-04-12; Completion date: 2018-08-09
Enrollment: 11 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Background:

\- Adrenocortical carcinoma (ACC) is a rare tumor of the adrenal gland. Few people who develop this disease live more than 5 years after being diagnosed. Those whose tumors have spread inside their abdomen may have an especially poor outcome. In these cases, traditional chemotherapy is not very effective. One possible new treatment is aggressive surgery with heated chemotherapy. This type of treatment has been more effective for other types of cancer in the abdomen. Researchers want to see this if approach can improve the outcomes of people with ACC.

Objectives:

\- To test the safety and effectiveness of surgery and heated chemotherapy for ACC.

Eligibility:

\- Individuals at least 18 years of age who have advanced ACC.

Design:

* Participants will be screened with a physical exam and medical history. Blood samples will be collected. Heart function tests will be given. Imaging studies will be used to locate the surgical sites before the operation.
* Participants will have surgery to remove ACC tumor tissue. After the tumors have been removed, they will have heated chemotherapy with cisplatin. The heat may help weaken any remaining cancer cells and make them easier to destroy. It will also focus the treatment on the tumor sites, rather than the whole body.
* Participants will recover in the hospital for several days after surgery. They will have regular follow-up visits to monitor the outcome of the surgery.

Detailed description:
Background:

* Adrenocortical carcinoma (ACC) is a rare tumor with an incidence of 1.5 to 2 per million people per year and has a very poor prognosis with an overall 5-year mortality rate of 75 - 90% and an average survival from the time of diagnosis of 14.5 months.
* The treatment of choice for a localized primary or recurrent tumor is surgical resection. For unresectable metastatic or recurrent disease, mitotane, aminoglutethimide, metapyrone, and ketoconazole are used.
* Cisplatin is one of the most effective chemotherapeutic agents for ACC. In the Surgery Branch we have conducted Phase I and II trials using heated intraperitoneal (IP) chemotherapy with cisplatin for primary peritoneal mesothelioma, low grade appendiceal adenocarcinoma, ovarian malignancies, and high grade adenocarcinoma of the gastrointestinal tract. Synergy has been demonstrated for cisplatin and hyperthermia.
* The purpose of this trial is to determine if an aggressive surgical approach with intraperitoneal administration of heated cisplatin when tumor volume is minimal, can impact and improve on progression free survival.

Objectives:

\- To determine IP progression free survival after optimal debulking and heated IP chemotherapy with cisplatin in patients with IP spread of adrenocortical cancer

Eligibility:

\- Histologically proven ACC evaluable by computed tomography (CT) imaging with the majority of disease confined to the peritoneal cavity and surgically resectable to a residual size of less than 1 cm or amenable to radiofrequency ablation in patients who are \> 18 years of age.

Design:

\- This is a classic phase 2 trial to determine efficacy of this therapeutic strategy in ACC. Patients will undergo cytoreductive surgery to achieve a CCR of 0 or 1.

Patients who are successfully debulked will then undergo hyperthermic intraperitoneal chemotherapy (HIPEC) with cisplatin.

Patients will be evaluated by associate investigators in coordination with the Principal Investigator for eligibility. Due to its exploratory nature, up to 30 patients may be enrolled to obtain 24 evaluable patients. (Patients must undergo successful debulking and HIPEC to be considered evaluable.)

Arms: arm 1: Cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy (HIPEC) with cisplatin
Interventions: intervention 1: Cisplatin intervention 2: Cytoreductive surgery intervention 3: sodium thiosulfate
Intervention descriptions: intervention 1: Patients who are successfully debulked will then undergo hyperthermic intraperitoneal chemotherapy (HIPEC) with cisplatin. intervention 2: Patients will undergo cytoreductive surgery to achieve a Completeness of Cytoreduction Score (CC) of 0 or 1. intervention 3: sodium thiosulfate will be given to limit the toxicity of cisplatin

Protocol documents:
Prot_SAP_000.pdf: 
Abbreviated Title: HIPEC for ACC 
Version Date: 08/18/2017 
 
 
 
1 
Abbreviated Title: HIPEC for ACC 
CC Protocol #: 13-C-0114 E 
Version date: 08/18/2017 
NCT number: NCT01833832 
Title: Phase II Trial of Surgical Resection and Heated Intraperitoneal Peritoneal Chemotherapy 
(HIPEC) for Adrenocortical Carcinoma 
 
Principal Investigator:  
 
Jeremy Davis, MD 
A-F 
 
 
Thoracic and GI Oncology Branch, NCI 
 
  10 Center Drive, CRC 4-3760 
 
  
Bethesda, MD 20892 
 
  Phone: 240-760-6229 
 
 
jeremy.davis@nih.gov 
NIH Associate Investigators:  
Udo Rudloff, MD, TGIB/CCR/NCI 
A-F 
  
  
  
  
 
Cara Kenney, RN, OCD/CCR/NCI 
A-C, E-F  
  
  
  
  
 
Dan Zlott, Pharm.D, Pharm/CC/NIH 
A-B 
  
  
  
  
 
Seth M. Steinberg, PhD,  BDMS/CCR/NCI 
B, E-F 
  
  
  
  
 
Maria Merino, MD, LP/CCR/NCI 
B, E-F 
  
  
  
  
 
Tricia Kunst, RN, OCD/CCR/NCI A-C, E-F 
Referral Contact/ 
Study Coordinator:    
 
Cara Kenney, RN, OCD/CCR/NCI 
  
  
  
  
10 Center Drive, CRC 4-3752 
  
  
  
  
Bethesda, MD 20892 
  
  
  
  
Phone: 240-760-6233 
  
  
  
 
Email:  kenneycara@mail.nih.gov 
Non-NIH Associate Investigators: Tatiana Beresnev, ** Leidos Biomedical Research 
B 
  
  
  
  
  
Yvonne Shutack, CRA**, Leidos Biomedical Research 
B 
                                                            Marybeth Hughes, MD
 E-G, Eastern Virginia Medical 
                                                            School                                                        
 
** Not responsible for patient care 
Investigator Roles: 
A. Obtain information by intervening or interacting with 
living individuals for research purposes 
B. Obtaining identifiable private information about living 
individuals 
C. Obtaining the voluntary informed consent of individuals 
to be subjects 
D. Makes decisions about subject eligibility 
E. Studying, interpreting, or analyzing identifiable private 


Abbreviated Title: HIPEC for ACC 
Version Date: 08/18/2017 
 
 
 
2 
information or data/specimens for research purposes 
F. Studying, interpreting, or analyzing de-identified data or 
specimens for research purposes 
G. Some/all research activities performed outside NIH 
Commercial Agent: Cisplatin 
 


Abbreviated Title: HIPEC for ACC 
Version Date: 08/18/2017 
 
 
 
3 
PRECIS 
Background: 
• Adrenocortical carcinoma (ACC) is a rare tumor with an incidence of 1.5 to 2 per million 
people per year and has a very poor prognosis with an overall 5-year mortality rate of 75 
- 90% and an average survival from the time of diagnosis of 14.5 months. 
• The treatment of choice for a localized primary or recurrent tumor is surgical resection.  
For unresectable metastatic or recurrent disease, mitotane, aminoglutethimide, 
metapyrone, and ketoconazole are used. 
• Cisplatin is one of the most effective chemotherapeutic agents for ACC. In the Surgery 
Branch we have conducted Phase I and II trials using heated intraperitoneal (IP) 
chemotherapy with cisplatin for primary peritoneal mesothelioma, low grade appendiceal 
adenocarcinoma, ovarian malignancies, and high grade adenocarcinoma of the 
gastrointestinal tract.  Synergy has been demonstrated for cisplatin and hyperthermia 
• The purpose of this trial is to determine if an aggressive surgical approach with 
intraperitoneal administration of heated cisplatin when tumor volume is minimal, can 
impact and improve on progression free survival. 
Objective: 
• To determine IP progression free survival after optimal debulking and heated IP 
chemotherapy with cisplatin in patients with IP spread of adrenocortical cancer 
Eligibility:  
• Histologically proven ACC evaluable by CT imaging with the majority of disease 
confined to the peritoneal cavity and surgically resectable to a residual size of less than 1 
cm or amenable to radiofrequency ablation in patients who are > 18 years of age. 
Design: 
• This is a classic phase 2 trial to determine efficacy of this therapeutic strategy in ACC. 
Patients will undergo cytoreductive surgery to achieve a CCR of 0 or 1.  Patients who are 
successfully debulked will then undergo HIPEC with cisplatin.  Patients will be evaluated 
by associate investigators in coordination with the Principal Investigator for eligibility. 
Due to its exploratory nature, up to 30 patients may be enrolled to obtain 24 evaluable 
patients. (Patients must undergo successful debulking and HIPEC to be considered 
evaluable.)  
 


Abbreviated Title: HIPEC for ACC 
Version Date: 08/18/2017 
 
 
 
4 
TABLE OF CONTENTS 
PRECIS 
................................................................................................
........................................... 3 
TABLE OF CONTENTS 
................................................................................................................ 4
 
1 INTRODUCTION 
................................................................................................................... 6
 
 Study objectives 
............................................................................................................... 6 
 Background and Rationale 
............................................................................................... 6 
2 ELIGIBILITY ASSESSMENT AND ENROLLMENT 
......................................................... 9
 
 Eligibility Criteria ............................................................................................................ 9
 
 Screening Evaluation...................................................................................................... 11
 
 Registration Procedures.................................................................................................. 12 
 Stratification Procedures 
................................................................................................ 12
 
3 STUDY IMPLEMENTATION 
............................................................................................. 12
 
 Study Design 
.................................................................................................................. 12
 
 Preoperative Patient Management 
.................................................................................. 12
 
 Patient Management in the Operating Room 
................................................................. 13 
 Peritoneal metastasectomy and cytoreductive surgery................................................... 13
 
 Intraperitoneal Chemotherapy HIPEC 
........................................................................... 13 
 Medications 
.................................................................................................................... 14
 
 Post-Operative Care 
....................................................................................................... 14
 
 Research Evaluations 
..................................................................................................... 15
 
 Discharge 
........................................................................................................................ 15
 
 Post Discharge 
................................................................................................................ 15 
 Treatment Assessment and Response (Follow up period) 
............................................. 15 
 Measurement of Health Related Quality of Life 
............................................................ 16
 
 Criteria for Removal from Protocol Therapy and Off Study Criteria 
............................ 17
 
4 CONCOMITANT MEDICATIONS/MEASURES 
............................................................... 18
 
5 BIOSPECIMEN COLLECTION .......................................................................................... 18
 
6 DATA COLLECTION AND EVALUATION 
..................................................................... 18
 
 Data Collection 
............................................................................................................... 18
 
 Routine Data Reporting 
.................................................................................................. 18 
 Adverse Events 
............................................................................................................... 19
 
7 SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN
  19
 


Abbreviated Title: HIPEC for ACC 
Version Date: 08/18/2017 
 
 
 
5 
 Definitions 
...................................................................................................................... 19
 
 NCI-IRB AND CLINICAL DIRECTOR Reporting 
...................................................... 21
 
 Data and Safety Monitoring Plan 
................................................................................... 22
 
8 STATISTICAL CONSIDERATIONS 
.................................................................................. 22
 
9 HUMAN SUBJECTS PROTECTION 
.................................................................................. 23
 
 Rational for Subject Selection 
........................................................................................ 23
 
 Participation of Children 
................................................................................................ 23
 
 Participation of Subjects Unable to Give Consent 
......................................................... 23 
 Evaluation Benefits and Risks/Discomforts 
................................................................... 23
 
 Risks/Benefit Analysis 
................................................................................................... 24
 
 Consent Process and Documentation 
............................................................................. 24 
10 PHARMACEUTICAL INFORMATION 
............................................................................. 25
 
 Cisplatin (CDDP) 
........................................................................................................... 25
 
 Sodium Thiosulfate 
........................................................................................................ 26 
11 REFERENCES 
...................................................................................................................... 28
 
12 APPENDICES 
....................................................................................................................... 31
 
 Appendix A: Peritoneal Cancer Index ........................................................................... 31
 
 Appendix B: ECOG Performance Status 
....................................................................... 32 
 Appendix C: Health Related Quality of Life ................................................................. 33 
 Appendix D: Completeness of Cytoreduction Score 
..................................................... 34 
 
 
 


Abbreviated Title: HIPEC for ACC 
Version Date: 08/18/2017 
 
 
 
6 
 
1 INTRODUCTION  
 STUDY OBJECTIVES 
   Primary Objective 
• To determine intraperitoneal progression free survival after optimal debulking and heated 
intraperitoneal chemotherapy with cisplatin in patients with intraperitoneal spread of 
adrenocortical cancer 
   Secondary Objectives 
• Determine morbidity of this procedure in this patient population 
• Determine the impact of surgery and HIPEC on QOL 
• Determine the impact of surgery and HIPEC on hormone excess 
• Examine patterns of recurrence (local versus systemic) 
• Perform molecular analyses to try to discern if there are intrinsic differences between 
tumors that recur widely throughout the peritoneal surface and those that metastasize to 
other organs or are confined to a local recurrence. 
• Determine overall survival after optimal debulking and heated intraperitoneal 
chemotherapy with cisplatin in patients with intraperitoneal spread of adrenocortical 
cancer. 
 BACKGROUND AND RATIONALE 
 Adrenocortical Carcinoma 
Adrenocortical carcinoma (ACC) is a rare tumor with an incidence of 1.5 to 2 per million people 
per year1-3.  It has a very poor prognosis with an overall 5-year mortality rate of 75 - 90% and an 
average survival from the time of diagnosis of 14.5 months. Signs and symptoms due to excess 
hormonal secretion are seen in a large fraction of patients, further contributing to the morbidity 
associated with this disease.  
The treatment of choice for a localized primary or recurrent tumor is surgical resection. 
Excisable primary tumors represent about 40% of cases at presentation; however, 60 - 80% of 
these patients eventually die from recurrent extensive metastases
4. Patients with recurrent or 
metastatic disease are infrequently curable by surgery alone due to the propensity for 
intraperitoneal recurrence.  
For unresectable metastatic or recurrent disease, mitotane, aminoglutethimide, metapyrone, and 
ketoconazole are used.  Of these, mitotane is the only agent with both anti-tumor and adrenolytic 
effects. Aminoglutethimide, metapyrone, and ketoconazole are used to treat the symptoms of 
excess hormone production in patients with functional tumors. Mitotane, the most extensively 
studied agent, was reported to have response rates of 30-60% in older studies without 
standardized response criteria or the use of modern imaging technology
5-7. Response rates of 
20% or less have been noted with more modern imaging technology. These responses persist for 
an average of 10.5 months with no apparent impact on overall survival. 
Most reports of cytotoxic therapy for ACC are anecdotal or include a small number of patients8-
13. These studies report low response rates with the majority of responses classified as partial and 


Abbreviated Title: HIPEC for ACC 
Version Date: 08/18/2017 
 
 
 
7 
of less than one year in duration. Trials using mitotane in combination with various 
chemotherapeutic agents have had similar results
12, 13. The largest randomized trial for metastatic 
or locally advanced ACC conducted was recently published and showed that a regimen of 
etoposide, doxorubicin and cisplatin (EDP) combined with mitotane was superior to the 
combination of stroptozocin and mitotane with a median PFS of  5.0 months vs. 2.1 months and 
response rate of 23.2 and 9.2% respectively
14.  
A retrospective analysis was performed on fourteen patients with peritoneal predominant 
recurrences who were treated with EDP by Dr. Fojo’s group at the NCI. Patients who did not 
respond to chemotherapy survived an average of 14 months following treatment; patients who 
demonstrated a response to the chemotherapy survived for an average of 30 months. While 
small, the numbers seem to indicate that response to chemotherapy may correlate with an 
increase in survival. Intraperitoneal chemotherapy allows the administration of high doses of 
chemotherapy directly to the tumor bed and thus may improve the progression free survival as 
well as overall survival in this patient population. 
Dr. Fojo’s group has also accumulated a large data base on metastatic adrenal cancer that 
includes whole exome sequence, as well as cDNA and microRNA array data. Preliminary data 
has shown a high level of expression of the chemokine receptor, CXCR4, on the membrane of 
adrenal cancer cells, and expression of the receptor
's ligand, CXCL12 (SDF1) on the peritoneal 
surface. Because this finding may lead to a therapeutic option in the future, it will be further 
investigated during the course of this study as listed below.  
 Enumeration of Circulating Endothelial Cells (CEC) 
Early increase of CEC following anti-angiogenic drug administration can be an interesting 
marker of treatment efficacy. Interpretation of CEC change must take into account multiple 
factors such as the mechanism of drug action, time of CEC measurement to drug administration, 
phenotype of CEC quantified. Theoretically, various antigens can be used to characterize mature 
CEC. In general CD45 expression is used to exclude hematopoietic cells, and CD133 to exclude 
immature cells. Commonly used endothelial markers include CD31, CD146, CD34, CD144 or 
CD105. However, there is a lack of consensus regarding combination of these markers to 
characterize CEC by flow cytometry analysis. In this study, we will evaluate pre- and post-
treatment changes in mature circulating endothelial cells (CD 146+, CD133-), as determined by 
flow cytometry analysis. This evaluation will be conducted in Dr. Jane Trepel’s lab, 
NIH/NCI/MOB. CEC may be collected (16ml in CPT blue/black tubes) pre surgery, at 6 weeks 
(+/- 2 weeks) and 6 months (+/- one month).  
During the course of this study, tissue will be procured at the time of surgery and will undergo 
molecular analysis in order to try to discern if there are intrinsic differences between tumors that 
recur widely throughout the peritoneal surface and those that metastasize to other organs or are 
confined to a local recurrence. 
 HIPEC for ACC 
Cisplatin is one of the most effective chemotherapeutic agents for ACC. In the Surgery Branch 
we have conducted Phase I and II trials using heated intraperitoneal chemotherapy with cisplatin 
for primary peritoneal mesothelioma, low grade appendiceal adenocarcinoma, ovarian 
malignancies, and high grade adenocarcinoma of the gastrointestinal tract. Synergy has been 
demonstrated for cisplatin and hyperthermia15 and this was the basis for exploring the continuous 


Abbreviated Title: HIPEC for ACC 
Version Date: 08/18/2017 
 
 
 
8 
hyperthermic peritoneal perfusion with cisplatin in our initial Phase I trial.  The dose-limiting 
toxicity in that trial was renal insufficiency related to systemic absorption of cisplatin and 
occurred at a dose of 350 mg/M2.  All subsequent Surgery Branch trials using Cisplatin as the 
HIPEC agent were conducted using 250 mg/m2 with a thiosulfate bolus given 20 minutes before 
adding cisplatin to the intraperitoneal perfusate followed by continuous infusion of thiosulphate 
for an additional 12 hours.  
We have used heated cisplatin in different histologies including primary peritoneal 
mesothelioma, low grade mucinous adenocarcinoma (including low grade mucinous neoplasms 
of borderline malignant potential), and adenocarcinoma of gastrointestinal tract origin however, 
the majority of our experience has been in intraperitoneal mesothelioma and low grade 
appendiceal adenocarcinoma.  Phase II trials using cisplatin in both peritoneal mesothelioma and 
ACC have demonstrated some efficacy indicating potential similarity in the sensitivity of these 
histologies to cisplatin9-12, 16-18.  In our studies, patients with peritoneal mesothelioma achieved 
an average PFS of 17 months
19 with younger age and completeness of resection being predictive 
of better outcomes.  
 Peritoneal carcinomatosis  
Peritoneal carcinomatosis represents a formidable treatment challenge in oncology. Once 
considered a variant of systemic spread of disease, peritoneal carcinomatosis of most histologies 
is treated with palliative systemic chemotherapy alone, with surgery reserved only for palliation 
of disease- or treatment for related secondary events such as bowel obstruction and ascites. 
Systemic multi-drug chemotherapy has not altered the natural history of peritoneal 
carcinomatosis in more common diseases such as colorectal cancer, as patients suffer disease 
progression and functional deterioration due to visceral obstruction, malignant ascites and cancer 
cachexia over a matter of months
20-22.  The biology of peritoneal carcinomatosis is distinctive, 
unlike hematogenous metastasis.  Insights into the natural history of peritoneal tumor 
dissemination have engendered novel multi-modality treatment approaches to this challenging 
clinical problem. Tumor dissemination across peritoneal surfaces occurs through established 
mechanisms of direct tumor extension; tumor cell spread in peritoneal fluid, and malignant 
peritoneal seeding from surgical manipulation of the tumor, and can occur in the absence of 
regional or distant nodal or systemic metastases.  
Adrenal neoplasms are one of the most common of all human tumors
23. The prevalence of 
adrenal incidentaloma is approximately 5% on abdominal imaging, but can be as high as 10% in 
the elderly. As the U.S. population ages, the management of adrenal incidentaloma will be an 
increasingly important issue in health care
23. There are no reliable preoperative clinical, imaging 
or biochemical tests available to distinguish between primary benign and malignant 
adrenocortical neoplasms in the absence of obvious metastatic disease or locoregional invasion
24. 
Imaging features such as tumor heterogeneity, irregular tumor border, hemorrhage, necrosis, 
rapid tumor growth rate, tumor Hounsfield unit >10-20 on non-contrast CT scan, and intravenous 
contrast washout of 40% or less after 15 minutes are more common in malignant tumors but are 
not reliable enough to avoid the need for adrenalectomy to exclude a cancer diagnosis nor to 
forgo continued follow up
24-29. The majority of patients undergo laparoscopic adrenalectomy for 
diagnosis.  ACC cannot be diagnosed by frozen section (postoperative histopathologic 
examination to distinguish between malignant and benign primary adrenal tumors is difficult) 
and thus peritoneal seeding from surgical manipulation is a particular problem with ACC as the 
procedure is performed without a tumor diagnosis30, 31.  


Abbreviated Title: HIPEC for ACC 
Version Date: 08/18/2017 
 
 
 
9 
According to a recent publication, the rate of peritoneal carcinomatosis following laparoscopy is 
30% at center experienced in laparoscopic procedures and 16% following open adrenalectomy. 
A European study suggests the 4 year rate of peritoneal carcinomatosis is 67% for laparoscopy 
and only 27% for open adrenalectomy. Due to increasing use of laparoscopy, this has evolved as 
a significant problem for patients with metastatic adrenocortical cancer.  The clinical sequela is 
vexing as the peritoneum is a surface that is not well penetrated by traditional systemic 
intravenous chemotherapy. Hyperthermia alone has been shown to be toxic to malignant cells 
and we have previously combined cisplatin and hyperthermia in prior protocols safely. 
  Surgical metastasectomy  
Surgical metastasectomy has been used extensively for ACC in our institution. Our published 
data and experience demonstrates the ability to safely perform this surgery and to prolong 
disease free interval to greater than a year in selected patients
32.  Combining surgery with 
Cisplatin, the drug most effective in ACC, seems like a logical direction for the treatment of this 
histology where the bulk of tumor is intraperitoneal. The purpose of this trial is to determine if an 
aggressive surgical approach with intraperitoneal administration of heated cisplatin when tumor 
volume is minimal, can impact and improve on progression free survival.  
Given the aggressive treatment regimen and the aggressive nature of the diseases, it is important 
to understand the impact this therapy has on patients’ health related quality of life. As a 
secondary endpoint we will therefore evaluate patients’ health related quality of life prior to 
therapy and at intervals following recovery from the surgery and HIPEC. The goal of tracking 
quality of life is while surgery may temporarily negatively impact on QOL, it is our hope that it 
would rebound to better than pre-op if this approach has any merit and utility in the care of 
patients in the future. 
2 ELIGIBILITY ASSESSMENT AND ENROLLMENT 
   E
LIGIBILITY CRITERIA 
 Inclusion Criteria 
• Histologically proven ACC with the majority of disease confined to the peritoneal cavity 
and resectable or amenable to radiofrequency ablation 
• Disease evaluable by CT or PET imaging 
• All disease should be deemed resectable based on imaging studies e.g.: 
o Hepatic metastases (unilateral or bilateral ≤ 5 lesions, ≤ 15 cm total diameter) 
o Note: Hepatic lesions must be amenable to complete resection 
o Primary peritoneal metastases (small disease load ≤ P2 disease) without massive 
ascites or intestinal obstruction 
o Lung metastases (≤ 3 unilateral/bilateral, 9 cm total diameter) 
o Note: lung lesions must be amenable to complete resection 
o Note: Patients with both pulmonary and hepatic metastases will be enrolled at the 
discretion of the PI 
o Note: In situations where resection to Completeness of Cytoreduction Score (CC) 
0 or 1 is uncertain, patients may undergo diagnostic laparoscopy prior to 
enrollment to determine feasibility of resection. (Appendix D) 
• Greater than or equal to 18 years of age 
• Able to understand and sign the Informed Consent Document 


Abbreviated Title: HIPEC for ACC 
Version Date: 08/18/2017 
 
 
 
10 
• Clinical performance status of ECOG ≤ 2 
• Life expectancy of greater than three months 
• Patients of both genders must be willing to practice birth control during and for four 
months after receiving chemotherapy 
• Hematology: 
o Absolute neutrophil count greater than 1500/mm3 without the support of 
Filgrastim. 
o Platelet count greater than 75,000/mm3. 
o Hemoglobin greater than 8.0 g/dl. 
• Chemistry: 
o Serum creatinine less than or equal to 1.5 mg/dl unless the measured 
creatinine clearance is greater than 60 mL/min/1.73 m2 
o serum AST and ALT within 5 times the upper limit of normal and a total 
serum bilirubin of less than 3 times the upper limit of normal, both of which 
define the upper limit of grade 2 treatment related toxicities.  
o PT within 2 seconds of the upper limit of normal (INR≤1.8) 
• Recovered from any toxicity to grade 2 or less from all prior chemotherapy, 
immunotherapy or radiotherapy and be at least 30 days past the date of their last 
treatment with the exception of mitotane which may be continued. 
• Able to understand their disease and the exploratory nature of combining surgery and 
HIPEC for this histology. 
 Exclusion Criteria 
• Concomitant medical problems that would place the patient at unacceptable risk for a 
major surgical procedure. 
• History of congestive heart failure and/or an LVEF < 40%  
• Note: Patients at increased risk for coronary artery disease or cardiac dysfunction (e.g., 
>65yo, diabetes, history of hypertension, elevated LDL, first degree relative with 
coronary artery disease) will undergo full cardiac evaluation and will not be eligible if 
they demonstrate significant irreversible ischemia on stress thallium or an ejection 
fraction <40%. 
• Significant COPD or other chronic pulmonary restrictive disease with PFT’s indicating 
an FEV1 less than 50% or a DLCO less than 40% predicted for age  
Note: Patients who have shortness of breath with minimal exertion or who are at risk for 
pulmonary disease (e.g., chronic smokers) will undergo pulmonary function testing and 
will not be eligible if their FEV1 is < 50% of expected. 
• Grade 2 or greater neuropathy 
• Women of child-bearing potential who are pregnant or breastfeeding because of the 
potentially dangerous effects of the chemotherapy on the fetus or infant. 
• Brain metastases or a history of brain metastases 
• Childs B or C cirrhosis  
• Evidence of severe portal hypertension by history, endoscopy, or radiologic studies 
Note: Any diagnosis of portal hypertension or clinical stigmata of such including but not 
limited to gastric or esophageal varices, umbilical vein varices or telangectasias. 
• Weight < 30 kg  


Abbreviated Title: HIPEC for ACC 
Version Date: 08/18/2017 
 
 
 
11 
• Active systemic infections, coagulation disorders or other major medical illnesses of the 
cardiovascular, respiratory or immune system, myocardial infarction, cardiac 
arrhythmias, obstructive or restrictive pulmonary disease 
   S
CREENING EVALUATION  
 Within 6 weeks prior to treatment: 
• HIV, Hepatitis B surface antigen and Hepatitis C antibody  
• 12 lead EKG  
• Patients will undergo pulmonary function tests as indicated in section 2.1.2 
• Cardiac evaluation with possible stress test for patients with history of cardiac disease 
will be performed as indicated in section 2.1.2  
• ECHO if prior history of doxorubicin 
• Thoracic oncology consult for patients with pulmonary metastatases 
• Confirmation of pathology by the NCI Laboratory of Pathology [may be completed any 
time prior to enrollment] 
• Radionuclide bone scan, when clinically indicated 
• MRI Brain when indicated 
• PET-CT when indicated 
 Within 4 weeks prior to treatment 
• Baseline imaging: CT scan of chest, abdomen and pelvis (CT C/A/P) with triphasic 1mm 
cuts as per the liver scan protocol.  For patients with evidence of hepatic disease, a 
baseline MRI-L will be performed.   
• Completion of Health Related Quality of Life Forms (HRQOL) 
 Within 2 weeks prior to treatment 
• Complete history and physical examination including vital signs, height and weight as 
well as ECOG assessment. 
• Laboratory evaluation  
o CBC with platelets 
o Chem-20 (Sodium (Na), Potassium (K), Chloride (Cl), total CO2 (bicarbonate), 
Creatinine, Glucose, Urea nitrogen (BUN), Albumin, Calcium total, Magnesium 
total (Mg), Inorganic Phosphorus, Alkaline Phosphatase, ALT/GPT, AST/GOT, 
Total Bilirubin, Direct Bilirubin, LD, Total Protein, total CK,  
o C-reactive protein, Hg A1c, Ferritin, Prealbumin, 
o PT/PTT & INR,  
o Urinalysis 
• Tumor markers as indicated (serum cortisol, 24 hour urine for cortisol, ACTH, DHEA, 
and LDH) 
• Anesthesia consult  
 Within 1 week of surgical treatment: 
• Beta HCG for women of child bearing potential 


Abbreviated Title: HIPEC for ACC 
Version Date: 08/18/2017 
 
 
 
12 
 REGISTRATION PROCEDURES 
Authorized staff must register an eligible candidate with NCI Central Registration Office (CRO) 
within 10days of signing consent.  A registration Eligibility Checklist from the web site 
(http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) must be completed and sent via 
encrypted email to:  NCI Central Registration Office ncicentralregistration-l@mail.nih.gov.  
After confirmation of eligibility at Central Registration Office, CRO staff will call pharmacy to 
advise them of the acceptance of the patient on the protocol prior to the release of any 
investigational agents. Verification of Registration will be forwarded electronically via e-mail to 
the research team. A recorder is available during non-working hours.  
 STRATIFICATION PROCEDURES 
Patients will be stratified in to 2 groups: those with peritoneal recurrence only and those with 
visceral metastatic disease. 
3 STUDY IMPLEMENTATION 
 STUDY DESIGN 
This is a classic phase 2 trial to determine efficacy of this therapeutic strategy in ACC. Patients 
will undergo cytoreductive surgery to achieve a CC of 0 or 1.  Patients who are successfully 
debulked will then undergo HIPEC with cisplatin.  Patients will be evaluated by associate 
investigators in coordination with the Principal Investigator for eligibility. Due to its exploratory 
nature, up to 30 patients may be enrolled to obtain 24 evaluable patients. (Patients must undergo 
successful debulking and HIPEC to be considered evaluable.) 
NIH Advanced Directives Form: 
 As indicated in section 9.3, 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 
Surgical Guidelines:  
Note: The following guidelines are for the purpose of promoting consistency in the surgical 
procedure and perioperative care where possible.  Physician discretion will be exercised as 
necessary to ensure that the specific needs of the patient are met.  Details pertaining to surgical 
and perioperative management will be recorded in the patient medical record; only variables 
specified in section 6 will not be captured on the CRFs.  
 PREOPERATIVE PATIENT MANAGEMENT 
Patients will receive standard preoperative care as appropriate to the planned surgical 
intervention and the patient’s underlying health status which may include: 
• The day prior to surgery: Sequential Compression Devices (SCDS), incentive spirometry 
and appropriate bowel preparation regimen, and hydration  
• The night before operation: Hibiclens® shower 
• Beginning the night prior to the operation, the patients will be hydrated intravenously in 
preparation for the HIPEC with cisplatin. 


Abbreviated Title: HIPEC for ACC 
Version Date: 08/18/2017 
 
 
 
13 
Note: For patients undergoing hepatic resection, no anticoagulation will be given prior to 
operation. For patients receiving an epidural catheter heparin will not be given until the catheter 
has been successfully placed. 
  PATIENT MANAGEMENT IN THE OPERATING ROOM 
• Patients will receive perioperative antibiotics and the first dose will be administered prior 
to incision.  
• Epidural catheters should be considered in all patients. Decisions will be made by the 
anesthesiologist and the operating surgeon in full collaboration. 
• SCDs will be “on” before induction of anesthesia.  
• A central venous line, arterial line, and large bore catheters will be placed if blood loss is 
anticipated to be >500cc or at the discretion of the anesthesiologist in consultation with 
the surgeon. 
 PERITONEAL METASTASECTOMY AND CYTOREDUCTIVE SURGERY 
• If there is evidence that the extent of disease is beyond the ability to be cytoreduced such 
that the largest residual tumor nodule is > 1.0 cm, patients will not be considered for 
intraperitoneal cisplatin.   
• For patients with primary peritoneal metastases without massive ascites or intestinal 
obstruction, all visible disease will be resected if technically feasible. 
• Peritonectomy for patients with peritoneal disease includes the following: the right and 
left sub-diaphragmatic peritoneum, the falciform ligament, lesser and greater omentum, 
anterior, right and left abdominal wall down to the paracolic gutters and the pelvic 
peritoneum. 
• Partial (limited) peritonectomy for patients with intra-abdominal disease without 
peritoneal disease includes (i.e., liver metastases without peritoneal disease): peritoneal 
attachment of the hepatic left lateral segment and the spleen, 2 cm along the incision at 
the anterior abdominal wall and the falciform ligament 
• Organs may be resected en bloc if invaded by tumor. For example, the spleen is often 
involved in recurrent tumors from a left sided primary. Organs that may be resected 
include but are not limited to colon, small bowel, pancreas, spleen, and liver. 
• If a colonic anastomosis is required, a diverting ileostomy will be performed. This will be 
reversed after appropriate healing of the anastomosis. 
• After the cytoreduction has occurred and the patient is either a CCR 0 or CCR 1 then 
cisplatin heated intraperitoneal infusion will be conducted for 90 minutes at goals of at 
least 40°C.  
 INTRAPERITONEAL CHEMOTHERAPY HIPEC 
• Perfusion 
o Two large bore catheters will be inserted through the abdominal wall, one over 
the right lobe of the liver and one in the pelvis.  The abdominal fascia will be 
closed, and the catheters connected to a perfusion circuit.   
o The perfusion flow rate will be maintained at approximately 1.0 L/min as 
tolerated and a perfusate volume will be maintained which moderately distends 
the abdominal cavity this volume will vary depending on the amount of ascites in 
any given patient. 


Abbreviated Title: HIPEC for ACC 
Version Date: 08/18/2017 
 
 
 
14 
o Stable perfusion parameters are obtained and the peritoneal cavity is warmed to a 
minimum of 40° C prior to starting the clock for perfusion time.   
o The perfusion will be continued for 90 minutes.   
o During the perfusion, constant physical manipulation of the abdomen (shaking) 
will be maintained for the entire time to assure even distribution of the perfusate. 
o Peritoneal temperature will be measured continuously by three probes placed 
immediately beneath the peritoneal surface on either side of the abdomen and in 
the pelvis.   
o The patient’s core temperature will be measured with an esophageal probe (which 
correlates well with pulmonary artery temperatures) and maintained at less than 
41°C using a cooling blanket and ice packs as needed.   
o At the end of the perfusion, the abdomen will be re-opened and the perfusate 
irrigated from the abdominal cavity. 
 MEDICATIONS 
• Cisplatin will be calculated on ideal body weight (IBW).  Ideal body weight will be 
calculated based upon the following formula: 
IBW (male, in kg) = [(Height in inches – 60) x 2.3] + 50 
IBW (female, in kg) = [(Height in inches – 60) x 2.3] + 45.5 
• Cisplatin 250mg/m2 will be diluted in 1 liter of 0.9% sodium chloride for injection as 
described in Section 11.1.3 
• Sodium thiosulfate.  
o In order to limit the systemic toxicity of cisplatin, sodium thiosulfate will be 
administered by continuous intravenous infusion starting immediately prior to the 
perfusion and continuing for a total of 12 hours.    
o 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.   
o 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 over 12 hours by Infusion Pump. 
 POST-O
PERATIVE CARE 
 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 100cc/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). 
• Patients will receive routine post-operative care; early ambulation will be encouraged. 


Abbreviated Title: HIPEC for ACC 
Version Date: 08/18/2017 
 
 
 
15 
• Laboratory evaluations will include: 
o CBC, platelets, acute care, mineral and hepatic panel daily x 4 days and then 
every third day or as clinically indicated until discharge.  
o Tumor markers for new baseline will be obtained on the day of discharge as 
indicated.  
• Other evaluations 
o Imaging studies as clinically indicated. 
 RESEARCH EVALUATIONS 
• Circulating endothelial Cells may be collected - 16ml in CPT blue/black tubes  
o Within 1 month prior to surgery 
o 6 weeks (+/- 2 weeks) post surgery 
o Every 6 months (+/- one month) post surgery 
• Blood will be transported to: 
Jane Trepel - Cell Signaling Lab 
Room10/12n230 
301-496-1547 
 DISCHARGE  
• Total hospitalization may be approximately 7-14 days.   
• Patients who are discharged within this time frame should be able to tolerate an oral diet.  
Patients who have a prolonged hospitalization but are able to tolerate a diet may be 
discharged with home rehab/physical therapy.  
 POST DISCHARGE 
• CBC weekly following discharge or until toxicities have resolved (less than grade 3 or 
baseline) and patient has recovered from nadir.  This may be done through the patient’s 
referring physician with the results faxed to Dr. Hughes or her designee.   
• Patients will return to clinic approximately 4-8 weeks following surgery for their 1st 
post- operative visit and will be followed as clinically indicated until recovery.   Upon 
recovery from the surgical procedure, the following end of treatment evaluations will be 
performed: 
o Imaging studies to establish new baseline 
o Tumor markers as indicated 
o CBC, acute care, mineral and hepatic panel, CRP, Albumin, pre-albumin, ferritin, 
Hgb A1c if elevated pre-op. 
o Physical examination to include ECOG, weight and vital signs 
o QOL survey 
 TREATMENT ASSESSMENT AND RESPONSE (F
OLLOW UP PERIOD) 
• Because of the nature of peritoneal imaging and because cytoreductive surgery will likely 
eliminate all imageable disease, response can only be measured in terms of radiographic 
disease-free survival.  At any time point when there is evidence of progressive disease 
(imageable tumor nodules or increasing ascites persistent on CT scans as interpreted by 
the official interpretation of the imaging studies) the patients will be scored as 
progressive disease.  In some cases this may require successive scans, but the time of 


Abbreviated Title: HIPEC for ACC 
Version Date: 08/18/2017 
 
 
 
16 
recurrence will be retrospectively defined at the point the first scan demonstrated 
imageable disease.  
• Patients will be evaluated 3 months from the operative date (+/- 1 month) intervals for the 
first year; every four months for (+/- 1 month) the next year and then q 6 months (+/- 1 
month) thereafter. 
• The following evaluations will be performed at each visit: 
o Imaging studies 
o Physical examination to include ECOG, weight and vital signs 
o Tumor markers as indicated 
o CBC, acute care, mineral and hepatic panel, CRP, Albumin, pre-albumin, ferritin, 
Hgb A1c if elevated pre-op. 
o Completion of Health related Quality of Life Forms (HRQOL) – at the first 
follow up visit and then at each evaluation until off study.  
• Patients who are unwilling or unable to return for follow up evaluation will be followed 
every 6 months by phone contact until off study criteria are met. The following 
information may be obtained: 
o Summary of treatment received since the previous contact 
o Estimation of ECOG status 
o Request for imaging studies, physical exam and laboratory reports to be sent to 
the PI 
Note: if patient is taken off study prior to 1 year following surgery, the HRQOL will be 
completed at the off study evaluation if possible.  
 MEASUREMENT OF HEALTH RELATED QUALITY OF LIFE 
Baseline Quality of Life Questionnaires (QOL) will be completed prior to the surgical procedure 
during the first follow up visit [following recovery from the surgical procedure] approximately 
one year following the procedure or at the time off study.   
Patients will be informed of the details of the QOL part of this study and reassured that their 
decision to participate will not affect their participation in the protocol.  Once enrolled, the 
patient has the right at any time to elect not to continue completing the questionnaires.  In the 
event a patient goes off study prior to completion of the follow up time points, the data gathered 
from their completed QOL questionnaires will be included in the final analysis. 
Measures will be initially administered by the Associate Investigator Research Nurse or designee 
prior to randomization.  The Research Nurse will assess the patient’s ability to read, and if the 
patient is unable to read, it will not be administered. The Research Nurse or designee will 
administer the questionnaires providing a firm surface at a table or a clipboard and a pencil.  The 
patients will be directed to complete the questionnaires using the following instructions: 
We would like to better understand how you and other persons in this study feel, how well you 
are able to do your usual activities, and how you rate your health while you are participating in 
this research study.  To help us better understand these things about you and other persons 
participating in this study please complete this questionnaire about your quality of life.  This 
questionnaire should not take longer than 15 minutes to complete. 
The questionnaire is simple to fill out.  Be sure to read the instructions on the top of the 
questionnaire.  Remember, this is not a test and there are no right or wrong answers.  Choose 


Abbreviated Title: HIPEC for ACC 
Version Date: 08/18/2017 
 
 
 
17 
the response that best represents the way you feel.  I will quickly review the questionnaire 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 questionnaire.  Please fill out the questionnaire 
now.  Return the questionnaire to me when you have completed it.  We will be asking you to 
complete this again during some of your follow up visits.  If you have any questions, please ask.    
Once the patient has completed the questionnaire, the Research Nurse or designee, will review it 
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 3.11. 
The Research Nurse or designee will request that the patient complete the questionnaire prior to 
seeing the physician, as the interaction between the patient and physician may influence the 
patient’s answers to the questionnaire. In the event a patient is taken off study, patients will be 
asked to complete one last questionnaire (as appropriate to the point of withdrawal) and the data 
will be included in the analysis. 
 CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA 
Prior to documenting removal from protocol therapy, effort must be made to have all subjects 
complete a safety visit approximately 30 days following the last dose of study therapy. 
 Criteria for removal from protocol therapy    
• Inability to undergo HIPEC 
• Unwilling to comply with treatment regimen or prescribed follow-up 
• Completion of treatment phase 
• Positive pregnancy test 
 Off Study Criteria 
• Death 
• Disease progression requiring systemic therapy  
• Start of any therapeutic agent other than mitotane 
• Completed study follow-up period 
• Participant requests to be withdrawn from the study 
• Lost to follow up 
• PI decision to close the study 
 Off Protocol Therapy and Off Study Procedure 
Authorized staff must notify Central Registration Office (CRO) when a subject is taken off 
protocol therapy and when a subject is taken off-study. A Participant Status Updates Form from 
the web site (http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) main page must be 
completed and sent via encrypted email to:  NCI Central Registration Office  
ncicentralregistration-l@mail.nih.gov. 


Abbreviated Title: HIPEC for ACC 
Version Date: 08/18/2017 
 
 
 
18 
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.   
5 BIOSPECIMEN COLLECTION 
No specimens will be collected for future research purposes on this protocol.  Patients who are 
willing to have specimens collected for future research purposes will be co-enrolled on protocol 
13-C-0176. 
6 DATA COLLECTION AND EVALUATION 
 DATA COLLECTION 
The PI will be responsible for overseeing entry of data into an in-house password protected 
electronic system 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. All data obtained during the conduct of the protocol will be 
kept in secure network drives or in approved alternative sites that comply with NIH security 
standards. Primary and final analyzed data will have identifiers so that research data can be 
attributed to an individual human subject participant. 
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, the IRB will be notified. 
Data will not be distributed outside NIH without IRB notification. 
Dr. Hughes will continue to have access to the data for purposes of data analysis and publication 
when she is at Eastern Virginia Medical. She will also have access to the data via a secure flash 
drive.  It is also possible that data will be sent to her via encrypted email. Dr. Hughes’ 
involvement in this research is covered under the Federal Wide Assurance of the NIH. 
 ROUTINE DATA REPORTING 
 Laboratory events will be captured as follows 
• During hospitalization for surgical resection, only the admission labs, first morning labs 
drawn after 4am, and labs that support the diagnosis of a reportable event will be 
uploaded into C3D. 
• For laboratory values obtained at sites other than the NIH Clinical Center: only the 
following values (highest grade per cycle) will be captured in C3D: 
o Hemoglobin, total white blood cell count, absolute neutrophil count, platelet 
count 
o PTT, PT or INR 
o Creatinine, ALT, AST, Bilirubin (total and direct),  
o Any unexpected laboratory abnormality ≥ grade 2 possibly, probably or definitely 
related to the research 


Abbreviated Title: HIPEC for ACC 
Version Date: 08/18/2017 
 
 
 
19 
 Concomitant Measures and Medications 
• Only those medications that the patient is taking at baseline on a routine basis or 
medications that cause an AE will be captured in C3D.  [Thus onetime medications, PRN 
medications, and medications given to treat adverse events will not be captured in C3D.] 
• Vital signs will be captured once at baseline 
• Evaluations that are performed for clinical indications only will not be captured (e.g. 
daily chest x-rays during hospitalization, interim post op visits) 
 ADVERSE EVENTS 
All adverse events will be described in the source documents  
 The following adverse events of any grade will be captured in C3D:   
• Abscess formation 
• Fistula formation 
• Length of Stay (LoS) >14 days (LoS is defined as the time in days from the date of the 
procedure until the date that discharge criteria are met).   
NOTE:   If the discharge criteria date is not the same as the actual date of discharge, the date the 
patient met discharge criteria should be documented in CRIS.   
 Exclusions to Routine Adverse Event Reporting 
The following Adverse Events will be captured only in the source documents and will not be 
reported in C3D. 
• For the duration of the study  
o Laboratory values that do not support the diagnosis of a reportable event with the 
exception of noted events in section 6.3.2. 
o All grade 1 events  
• During hospitalization for surgical resection 
o Grade 1 and 2 events 
o Grade 3 and 4 events which resolve during the first 72 hours following surgery 
• Post-operative recovery phase (following discharge) 
o Grade 1 and 2 events 
o Events that result in a hospitalization for convenience will not be reported. 
• During the follow up period (more than 30 days following the last treatment) 
o Only those events that are serious, unexpected, and related to the treatment will be 
captured in C3D.  
7 SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING 
PLAN 
 DEFINITIONS 
 Adverse Event 
An adverse event is defined as any reaction, side effect, or untoward event that occurs during the 
course of the clinical trial associated with the use of a drug in humans, whether or not the event 
is considered related to the treatment or clinically significant. For this study, AEs will include 
events reported by the patient, as well as clinically significant abnormal findings on physical 


Abbreviated Title: HIPEC for ACC 
Version Date: 08/18/2017 
 
 
 
20 
examination or laboratory evaluation. A new illness, symptom, sign or clinically significant 
laboratory abnormality or worsening of a pre-existing condition or abnormality is considered an 
AE.  All AEs must be recorded on the AE case report form unless otherwise noted above in 
Section 6.3.2. 
All AEs, including clinically significant abnormal findings on laboratory evaluations, regardless 
of severity, will be followed until return to baseline or stabilization of event. Serious adverse 
events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of at least possibly related to the agent/intervention 
should be recorded and reported as per section 7.2.   
 Suspected adverse reaction 
Suspected adverse reaction means any adverse event for which there is a reasonable possibility 
that the drug caused the adverse event. For the purposes of safety reporting, ‘reasonable 
possibility’ means there is evidence to suggest a causal relationship between the drug and the 
adverse event. A suspected adverse reaction implies a lesser degree of certainty about causality 
than adverse reaction, which means any adverse event caused by a drug. 
 Unexpected adverse reaction 
An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in 
the investigator brochure or is not listed at the specificity or severity that has been observed; or, 
if an investigator brochure is not required or available, is not consistent with the risk information 
described in the general investigational plan or elsewhere in the current application. 
"Unexpected”, also refers to adverse events or suspected adverse reactions that are mentioned in 
the investigator brochure as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring with the 
particular drug under investigation. 
 Serious 
An Unanticipated Problem or Protocol Deviation is serious if it meets the definition of a Serious 
Adverse Event or if it compromises the safety, welfare or rights of subjects or others. 
 Serious Adverse Event  
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following: 
• Death, 
• A life-threatening adverse drug experience 
• Inpatient hospitalization or prolongation of existing hospitalization 
• Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• A congenital anomaly/birth defect. 
• Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may 
require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. 


Abbreviated Title: HIPEC for ACC 
Version Date: 08/18/2017 
 
 
 
21 
Note: Events that result in a hospitalization for convenience will not be reported. 
 Disability 
A substantial disruption of a person’s ability to conduct normal life functions. 
 Life-threatening adverse drug experience 
Any adverse event or suspected adverse reaction that places the patient or subject, in the view of 
the investigator or sponsor, at immediate risk of death from the reaction as it occurred, i.e., it 
does not include a reaction that had it occurred in a more severe form, might have caused death. 
 Protocol Deviation (NIH Definition) 
Any change, divergence, or departure from the IRB approved research protocol. 
 Non-compliance (NIH Definition) 
The failure to comply with applicable NIH Human Research Protections Program (HRPP) 
policies, IRB requirements, or regulatory requirements for the protection of human research 
subjects.  
 Unanticipated Problem 
Any incident, experience, or outcome that: 
• Is unexpected in terms of nature, severity, or frequency in relation to  
(a) the research risks that are described in the IRB-approved research protocol and 
informed consent document; Investigator’s Brochure or other study documents, and 
(b) the characteristics of the subject population being studied; AND 
• Is related or possibly related to participation in the research; AND 
• Suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 
 NCI-IRB AND CLINICAL DIRECTOR REPORTING 
 NCI-IRB and NCI CD Expedited Reporting of Unanticipated Problems and Deaths 
The Protocol PI will report in the NIH Problem Form to the NCI-IRB and NCI Clinical Director: 
• All deaths, except deaths due to progressive disease  
• All Protocol Deviations 
• All Unanticipated Problems 
• All non-compliance 
Reports must be received within 7 days of PI awareness via iRIS. 
 NCI-IRB Requirements for PI Reporting at Continuing Review 
The protocol PI will report to the NCI-IRB:  
1. A summary of all protocol deviations in a tabular format to include the date the deviation 
occurred, a brief description of the deviation and any corrective action. 
2. A summary of any instances of non-compliance 


Abbreviated Title: HIPEC for ACC 
Version Date: 08/18/2017 
 
 
 
22 
3. A tabular summary of the following adverse events: 
• All Grade 2 unexpected events that are possibly, probably or definitely related to 
the research;  
• All Grade 3 and 4 events that are possibly, probably or definitely related to the 
research;  
• All Grade 5 events regardless of attribution;  
• All Serious Events regardless of attribution.  
NOTE: Grade 1 events are not required to be reported 
 DATA AND SAFETY MONITORING PLAN 
 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.  
All data will be collected in a timely manner and reviewed by the principal investigator or a lead 
associate investigator. Adverse events will be reported as required above. Any safety concerns, 
new information that might affect either the ethical and or scientific conduct of the trial, or 
protocol deviations will be immediately reported to the IRB using iRIS.  
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 this trial is to conduct a pilot study to determine if the use of debulking 
surgery and HIPEC in patients with intra-peritoneal spread of adrenocortical carcinoma is able to 
be associated with an intra-peritoneal progression free interval which may exceed that of the use 
of chemotherapy alone. 
Data from a recently published study indicated that a 5.0 month median PFS
14 may be attained in 
similar patients using EDP and mitotane. This will be a single arm trial with the goal of seeing if 
the proposed combination of HIPEC and surgery may be associated with a 10 month median 
PFS. Using the method of Brookmeyer and Crowley33, the study will plan to enroll 24 fully 
evaluable patients over a 60 month period. Based on this method, with 24 subjects, there would 
be 80% power to determine if there is a median PFS of 10 months rather than 5 months, based on 
a one-tailed 0.10 alpha level test. In practice, Kaplan-Meier curves and appropriate confidence 
intervals at selected time points will be provided to help interpret the results relative to historical 
results. 
At the rate of 6 patients per year, 24 evaluable patients could be enrolled in 5 years, allowing for 
a ceiling of 30 patients to account for patients who may be inevaluable. 


Abbreviated Title: HIPEC for ACC 
Version Date: 08/18/2017 
 
 
 
23 
9 HUMAN SUBJECTS PROTECTION 
 RATIONAL FOR SUBJECT SELECTION 
The investigational nature and objectives of this trial, the procedure and the treatments involved, 
the attendant risks and discomforts, potential benefits and potential alternative therapies will be 
carefully explained to the patient in the clinic setting and in the hospital prior to treatment and 
prior to obtaining a signed Informed Consent. This is particularly important for this study 
because of the relatively unique nature by which the treatment is given.  That is to say, the 
patients must subject themselves to a major operative procedure with the attendant risks and 
complications associated with it in order to receive treatment without any assurance of benefit 
from the treatment. 
 PARTICIPATION OF CHILDREN 
The surgical regimen used in this protocol is a major procedure which entails serious discomforts 
and hazards for the patient, such that fatal complications are possible.  It is therefore only 
appropriate to carry out this experimental procedure in the context of life threatening 
adrenocortical carcinoma.  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 adrenocortical carcinoma, 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.  
 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 9.5), 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 for evaluation.  For those subjects that become 
incapacitated and do not have pre-determined substitute decision maker, the procedures 
described in MAS Policy 87-4 for appointing a surrogate decision maker for adult subjects who 
are (a) decisionally impaired, and (b) who do not have a legal guardian or durable power of 
attorney, will be followed. 
 EVALUATION BENEFITS AND RISKS/D
ISCOMFORTS 
The potential benefit to patients undergoing this therapy would be palliation in terms of 
preventing or delaying intra-abdominal tumor progression and metastases elsewhere which can 
be a devastating and painful source of symptoms and cause for demise.  In addition, significant 
tumor response may extend progression free and overall survival.  The risks for this protocol 
include the risks associated with any abdominal surgery. This includes postoperative bleeding, 
intra-abdominal infection, enterocutaneous fistulas, anesthetic mishap and perioperative death.  
In addition, the toxicities of chemotherapy place the patients under risk.  A combination of 
surgery and chemotherapy may decrease healing at a time when healing of abdominal wounds 
and bowel anastomosis is essential for recovery.  All attempts will be made to avoid 


Abbreviated Title: HIPEC for ACC 
Version Date: 08/18/2017 
 
 
 
24 
enterotomies or a bowel resection where feasible.  In the case of intra-abdominal catastrophe 
after surgery, patients may require reoperation. 
 RISKS/B
ENEFIT ANALYSIS 
Patients with peritoneal carcinomatosis suffer with recurrent bowel obstructions, nausea, 
vomiting, crampy abdominal pain and incapacitating ascites.  This clinical scenario justifies 
aggressive treatment strategies as a means of palliation and survival benefit.  In Phase I and II 
trials we have seen long-term remissions after 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. 
There is a direct benefit to patients to stay on study during the follow up period because we 
follow them for disease recurrence. If or when we identify disease recurrence, we are often able 
to facilitate treatment, either on an NCI investigator protocol, or by referring to a colleague that 
treats the same disease process. 
Therefore, this protocol involves greater than minimal risk, but presents the prospect of direct 
benefit to individual subjects.  
 CONSENT PROCESS AND DOCUMENTATION 
All patients are thoroughly screened prior to initial consultation at the NIH.  This usually 
involves a telephone conversation between the patient and a physician or nurse associate 
investigator.  During the initial consultation the patient, along with family members, is presented 
a forthright and detailed overview of the treatment option available to them at the NIH.  The 
experimental nature of the treatment, its theoretical advantages and disadvantages, and an 
overview of the operative procedure and anticipated convalescence are presented.  The fact that 
the patient may undergo an operative procedure in order to receive therapy without any 
assurance of benefit, the aggressive nature of the treatment, and the likelihood of serious or 
potentially life-threatening complications are presented.  The Informed Consent document is 
given to the patient and they are asked to review it, make notes and follow-up with a phone call 
to the physician or nurse investigator to have any additional questions answered prior to 
considering treatment on protocol. 
When the patient is admitted to the Clinical Center for treatment, an associate physician 
investigator responsible for the care of the patient presents the previously described information 
in detail. The research nurse or Principal Investigator, or designee is responsible for obtaining 
consent from the patient upon admission.  The patient is reassured that participation on the trial 
is entirely voluntary and that they can withdraw or decide against treatment at any time without 
adverse consequences.  In fact, the investigators assure the patient that if alternate therapies are 
preferred that we will do all that we can to facilitate obtaining consultation and treatment from 
the appropriate medical center.  The signed consent will be verified by the physician responsible 
for the care of the patient.  The patient is asked to participate in completing the self-administered 
questionnaires measuring health related quality of life during this study.  They are assured that 
their eligibility to participate in the perfusion portion of this study is not dependent upon their 
willingness to complete the quality of life questionnaires. 


Abbreviated Title: HIPEC for ACC 
Version Date: 08/18/2017 
 
 
 
25 
 Re-consent via telephone 
The informed consent document will be sent to the subject.  An explanation of the study will be 
provided over the telephone after the subject has had the opportunity to read the consent form.  
The subject will sign and date the informed consent. A witness to the subject’s signature will 
sign and date the consent. 
The original informed consent document will be sent back to the consenting investigator who 
will sign and date the consent form with the date the consent was obtained via telephone.   
A fully executed copy will be returned via mail for the subject’s records. 
The informed consent process will be documented on a progress note by the consenting 
investigator and a copy of the informed consent document and note will be kept in the subject’s 
research record. 
 Informed consent of non-English speaking subjects 
If there is an unexpected enrollment of a research participant for whom there is no translated 
extant IRB approved consent document, the principal investigator and/or those authorized to 
obtain informed consent will use the Short Form Oral Consent Process as described in MAS 
Policy M77-2, and OHSRP SOP 12, 45 CFR 46.117 (b) (2).  The summary that will be used is 
the English version of the extant IRB approved consent document.  Signed copies of both the 
English version of the consent and the translated short form will be given to the subject or their 
legally authorized representative and the signed original will be filed in the medical record. 
Unless the PI is fluent in the prospective subject’s language, an interpreter will be present to 
facilitate the conversation (using either the long translated form or the short form). Preferably 
someone who is independent of the subject (i.e., not a family member) will assist in presenting 
information and obtaining consent. Whenever possible, interpreters will be provided copies of 
the relevant consent documents well before the consent conversation with the subject (24 to 48 
hours if possible).  
We request prospective IRB approval of the use of the short form process for non-English 
speaking subjects and will notify the IRB at the time of continuing review of the frequency of the 
use of the Short Form. 
10 PHARMACEUTICAL INFORMATION 
 CISPLATIN (CDDP) 
 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. 
 Stability/Storage 
After reconstitution with water for injection, USP, to a concentration of 1 mg/mL, cisplatin is 
stable at controlled room temperature (24
0C + 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.   


Abbreviated Title: HIPEC for ACC 
Version Date: 08/18/2017 
 
 
 
26 
 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.   
 Administration 
Cisplatin at a dose of 250 mg/M2 will be added to a stable perfusion system at a flow rate of 1.5 
- 2 L/min after draining an equivalent volume. 
 Toxicities 
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.   
 SODIUM THIOSULFATE 
 Formulation 
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.  It will be purchased commercially by the NIH 
Clinical Center Pharmacy Department. 
 Stability/Storage 
 The commercial formulation bears the manufacturer
's expiration date. 
 Preparation 
A loading dose of 7.5 gm/M2 of sodium thiosulfate will be diluted in 150 cc of 0.9% NS.  An 
additional 25.56 gm/M2 will be diluted in 1000 mL 0.9% sodium chloride for injection for 
maintenance infusion. 
 Administration 
Sodium thiosulfate will be given as an i.v. loading dose of 7.5 gm/M2 body surface area over 20 
minutes followed immediately by continuous i.v. maintenance infusion of 2.13 gm/M2/hr for 12 
hours delivered by IMED infusion pump.  The loading dose of sodium thiosulfate will be started 
immediately prior to beginning intraperitoneal CDDP administration. 


Abbreviated Title: HIPEC for ACC 
Version Date: 08/18/2017 
 
 
 
27 
 Toxicities 
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 hypobilemia presumably due 
to an osmotic diuretic effect. 
 


Abbreviated Title: HIPEC for ACC 
Version Date: 08/18/2017 
 
 
 
28 
11 REFERENCES 
  1.  Plager JE. Carcinoma of the adrenal cortex: clinical description, diagnosis, and treatment. 
Int Adv Surg Oncol 1984;7:329-353. 
  2.   Luton JP, Cerdas S, Billaud L et al. Clinical features of adrenocortical carcinoma, 
prognostic factors, and the effect of mitotane therapy. N Engl J Med 1990;322(17):1195-
1201. 
  3.   Third National Cancer Survey: incidence data. Natl.Cancer Inst.Monogr. i-x, 1-454. 1975. 
Ref Type: Generic 
  4.   Cohn K, Gottesman L, Brennan M. Adrenocortical carcinoma. Surgery 1986;100(6):1170-
1177. 
  5.   Lubitz JA, Freeman L, Okun R. Mitotane use in inoperable adrenal cortical carcinoma. 
JAMA 1973;223(10):1109-1112. 
  6.   Gutierrez ML, Crooke ST. Mitotane (o,p
'-DDD). Cancer Treat Rev 1980;7(1):49-55. 
  7.  Jarabak J, Rice K. Metastatic adrenal cortical carcinoma. Prolonged regression with 
mitotane therapy. JAMA 1981;246(15):1706-1707. 
  8.   Haq MM, Legha SS, Samaan NA, Bodey GP, Burgess MA. Cytotoxic chemotherapy in 
adrenal cortical carcinoma. Cancer Treat Rep 1980;64(8-9):909-913. 
  9.   Schlumberger M, Ostronoff M, Bellaiche M, Rougier P, Droz JP, Parmentier C. 5-
Fluorouracil, doxorubicin, and cisplatin regimen in adrenal cortical carcinoma. Cancer 
1988;61(8):1492-1494. 
 10.   van SH, van Oosterom AT. CAP (cyclophosphamide, doxorubicin, and cisplatin) regimen 
in adrenal cortical carcinoma. Cancer Treat Rep 1983;67(4):377-379. 
 11.   Johnson DH, Greco FA. Treatment of metastatic adrenal cortical carcinoma with cisplatin 
and etoposide (VP-16). Cancer 1986;58(10):2198-2202. 
 12.   Williamson SK, Lew D, Miller GJ, Balcerzak SP, Baker LH, Crawford ED. Phase II 
evaluation of cisplatin and etoposide followed by mitotane at disease progression in 
patients with locally advanced or metastatic adrenocortical carcinoma: a Southwest 
Oncology Group Study. Cancer 2000;88(5):1159-1165. 
 13.  Berruti A, Terzolo M, Pia A, Angeli A, Dogliotti L. Mitotane associated with etoposide, 
doxorubicin, and cisplatin in the treatment of advanced adrenocortical carcinoma. Italian 
Group for the Study of Adrenal Cancer. Cancer 1998;83(10):2194-2200. 
 14.   Fassnacht M, Terzolo M, Allolio B et al. Combination chemotherapy in advanced 
adrenocortical carcinoma. N Engl J Med 2012;366(23):2189-2197. 


Abbreviated Title: HIPEC for ACC 
Version Date: 08/18/2017 
 
 
 
29 
 15.   Barlogie B, Corry PM, Drewinko B. In vitro thermochemotherapy of human colon cancer 
cells with cis-dichlorodiammineplatinum(II) and mitomycin C. Cancer Res 
1980;40(4):1165-1168. 
 16.  Carteni G, Manegold C, Garcia GM et al. Malignant peritoneal mesothelioma-Results from 
the International Expanded Access Program using pemetrexed alone or in combination with 
a platinum agent. Lung Cancer 2009;64(2):211-218. 
 17.  Kim ST, Park JY, Lee J et al. The efficacy of the frontline platinum-based combination 
chemotherapy in malignant peritoneal mesothelioma. Jpn J Clin Oncol 2010;40(11):1031-
1036. 
 18.   Manegold C, Symanowski J, Gatzemeier U et al. Second-line (post-study) chemotherapy 
received by patients treated in the phase III trial of pemetrexed plus cisplatin versus 
cisplatin alone in malignant pleural mesothelioma. Ann Oncol 2005;16(6):923-927. 
 19.   Feldman AL, Libutti SK, Pingpank JF et al. Analysis of factors associated with outcome in 
patients with malignant peritoneal mesothelioma undergoing surgical debulking and 
intraperitoneal chemotherapy. J Clin Oncol 2003;21(24):4560-4567. 
 20.   Jayne DG, Fook S, Loi C, Seow-Choen F. Peritoneal carcinomatosis from colorectal 
cancer. Br J Surg 2002;89(12):1545-1550. 
 21.   Sadeghi B, Arvieux C, Glehen O et al. Peritoneal carcinomatosis from non-gynecologic 
malignancies: results of the EVOCAPE 1 multicentric prospective study. Cancer 
2000;88(2):358-363. 
 22.  Jacquet P, Vidal-Jove J, Zhu B, Sugarbaker P. Peritoneal carcinomatosis from 
gastrointestinal malignancy: natural history and new prospects for management. Acta Chir 
Belg 1994;94(4):191-197. 
 23.   Kloos RT, Gross MD, Francis IR, Korobkin M, Shapiro B. Incidentally discovered adrenal 
masses. Endocr Rev 1995;16(4):460-484. 
 24.   Sturgeon C, Kebebew E. Laparoscopic adrenalectomy for malignancy. Surg Clin North Am 
2004;84(3):755-774. 
 25.   Boland GW, Blake MA, Hahn PF, Mayo-Smith WW. Incidental adrenal lesions: principles, 
techniques, and algorithms for imaging characterization. Radiology 2008;249(3):756-775. 
 26.  Mayo-Smith WW, Boland GW, Noto RB, Lee MJ. State-of-the-art adrenal imaging. 
Radiographics 2001;21(4):995-1012. 
 27.   Pena CS, Boland GW, Hahn PF, Lee MJ, Mueller PR. Characterization of indeterminate 
(lipid-poor) adrenal masses: use of washout characteristics at contrast-enhanced CT. 
Radiology 2000;217(3):798-802. 


Abbreviated Title: HIPEC for ACC 
Version Date: 08/18/2017 
 
 
 
30 
 28.   Hamrahian AH, Ioachimescu AG, Remer EM et al. Clinical utility of noncontrast computed 
tomography attenuation value (hounsfield units) to differentiate adrenal 
adenomas/hyperplasias from nonadenomas: Cleveland Clinic experience. J Clin Endocrinol 
Metab 2005;90(2):871-877. 
 29.   Boland GW, Lee MJ, Gazelle GS, Halpern EF, McNicholas MM, Mueller PR. 
Characterization of adrenal masses using unenhanced CT: an analysis of the CT literature. 
AJR Am J Roentgenol 1998;171(1):201-204. 
 30.   Leboulleux S, Deandreis D, Al GA et al. Adrenocortical carcinoma: is the surgical 
approach a risk factor of peritoneal carcinomatosis? Eur J Endocrinol 2010;162(6):1147-
1153. 
 31.  Miller BS, Gauger PG, Hammer GD, Doherty GM. Resection of adrenocortical carcinoma 
is less complete and local recurrence occurs sooner and more often after laparoscopic 
adrenalectomy than after open adrenalectomy. Surgery 2012;152(6):1150-1157. 
 32.  Datrice NM, Langan RC, Ripley RT et al. Operative management for recurrent and 
metastatic adrenocortical carcinoma. J Surg Oncol 2012;105(7):709-713. 
 33.   Brookmeyer R, and Crowley J.J. A confidence interval for the median survival time. 
Biometrics 38, 29-41. 1982.  
Ref Type: Generic 
 
 
 
 


Abbreviated Title: HIPEC for ACC 
Version Date: 08/18/2017 
 
 
 
31 
12 APPENDICES 
 APPENDIX A: PERITONEAL CANCER INDEX 
 
 
 
 
 
 
  
 
 
 
 
 


Abbreviated Title: HIPEC for ACC 
Version Date: 08/18/2017 
 
 
 
32 
 APPENDIX B: ECOG PERFORMANCE STATUS 
Grade  
ECOG Performance 
 
0    
Fully active, able to carry on all pre-disease performance without restriction 
1   
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work 
2  
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  
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours 
4  
Completely disabled -cannot carry on any self-care. Totally confined to bed or 
chair 
5    
Dead 
 
 
 


Abbreviated Title: HIPEC for ACC 
Version Date: 08/18/2017 
 
 
 
33 
 APPENDIX C: HEALTH RELATED QUALITY OF LIFE  
The Functional Assessment of Cancer Therapy-Colorectal is a 36 item Likert-type survey of 27 
general questions divided into four domains (physical well-being [7 items], social/family well-
being [7 items], emotional well-being [6 items], and functional well-being [7 items]) appropriate 
for use with patients with any form of cancer and a cancer subscale of 9 questions specific for 
colon cancer or patients experiencing abdominal symptoms.  The time frame on which responses 
are based is “during the past seven days”.  The tool takes approximately 10 minutes to complete.  
Total score and specific subscale scores can be analyzed.  The reliability of the FACT-C 
demonstrates an alpha coefficient of 0.89, an overall test-retest reliability of .92.  Concurrent 
validity is supported by a strong correlation with the Functional Living Index-cancer (FLIC) 0.80 
and the self-administered version of the Quality of Life Index (QLI) 0.74.  Since this study will 
be measuring changes in quality of life over time in response to the cancer therapy, the selected 
tool must be sensitive to change.  The FACT-C has been analyzed correlating patient-reported 
performance ratings.  One way analyses of variance indicated an acceptable level of sensitivity to 
change. 
 
 


Abbreviated Title: HIPEC for ACC 
Version Date: 08/18/2017 
 
 
 
34 
 APPENDIX D: COMPLETENESS OF CYTOREDUCTION SCORE 
CC-0  
All visible tumors are removed during cytoreduction surgery, and there is no 
visible cancer in the abdomen at the completion of the surgery 
 
CC-1  
Tumor nodules remain in the abdomen or pelvis after surgery but are less than 
2.5mm in size 
 
CC-2  
Tumor nodules remain in the abdomen or pelvis and are between 2.5 mm and 2.5 
cm in size 
 
CC-3  
Tumor nodules greater than 2.5 cm of a confluence (merging) of non-removable 
tumor nodules remain at any site in the abdomen or pelvis after surgery 
 

ICF_001.pdf: 
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
INSTITUTE: 
National Cancer Institute 
STUDY NUMBER: 
13-C-0114 
PRINCIPAL INVESTIGATOR: 
Jeremy Davis, M.D. 
STUDY TITLE:  
Phase II Trial of Surgical Resection and Heated Intraperitoneal Peritoneal Chemotherapy 
(HIPEC) for Adrenocortical Carcinoma 
Continuing Review Approved by the IRB on 09/25/17 
Amendment Approved by the IRB on 09/23/17 (E)  
 
                            Date Posted to Web: 10/13/17 
Standard 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent (1) 
 
INTRODUCTION 
We invite you to take part in a research study at the National Institutes of Health (NIH). 
First, we want you to know that: 
Taking part in NIH research is entirely voluntary.  
You may choose not to take part, or you may withdraw from the study at any time.  In 
either case, you will not lose any benefits to which you are otherwise entitled.  However, 
to receive care at the NIH, you must be taking part in a study or be under evaluation for 
study participation. 
You may receive no benefit from taking part.  The research may give us knowledge that 
may help people in the future. 
Second, some people have personal, religious or ethical beliefs that may limit the kinds of 
medical or research treatments they would want to receive (such as blood transfusions).  If you 
have such beliefs, please discuss them with your NIH doctors or research team before you agree 
to the study. 
Now we will describe this research study.  Before you decide to take part, please take as much 
time as you need to ask any questions and discuss this study with anyone at NIH, or with family, 
friends or your personal physician or other health professional.   
Why is this study being done?  
Adrenocortical carcinoma (ACC) is a rare tumor that has a very poor prognosis; few 
patients diagnosed with this disease live beyond 5 years after being diagnosed.  Those 
whose tumors have spread throughout their abdomen have an especially poor prognosis 
and traditional chemotherapy is not very effective.   At the NIH Clinical Center, we have 
treated patients with other types of cancer whose tumors have spread throughout their 
abdomen with aggressive surgical removal of their tumors followed by heated 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 13-C-0114 
CONTINUATION: page 2 of 10 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
chemotherapy with good results. We think that this type of treatment may help patients 
with ACC.  In this study, we would like to determine if this type of surgery plus heated 
chemotherapy can improve survival in patients with ACC.  
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 ACC and 
although your tumor has spread throughout your abdomen, we think that we will be able to 
remove 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?  
Approximately 30 patients with ACC will take part in this study. 
Description of Research Study 
In this study patients will undergo a major surgical operation to remove as many of their visible 
cancer tumors as possible.  At the end of the surgical procedure, while still in the OR (and under 
general anesthesia) patients will receive heated intraperitoneal peritoneal chemotherapy with a 
drug called cisplatin (HIPEC). At the NIH Clinical Center, we have used surgery and HIPEC to 
treat patients with several different types of cancers that have spread to their abdominal organs.  
These have included gastric cancer, appendiceal cancer, peritoneal mesothelioma and other GI 
cancers that have spread to the peritoneum (the thin membrane that covers all of the abdominal 
organs).  Following the procedure, patients will likely remain in the hospital for 10-21 days and 
are then will be seen in clinic every few weeks following discharge until fully recovered. Patients 
will be asked to complete a Quality of Life Questionnaire several times throughout the study so 
that we can see how the procedure affects their quality of life. Patients will be followed for 
survival. 
Stage 
Timeframe 
Location 
Events 
Work up 
1-2 weeks 
Inpatient and out 
patient   
Scans, x-rays, labs, QOL 
questionnaire, other tests as needed 
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 tumors 
Follow up 
Every 3 months for 1 
year, then every 4 
months for 1 year, then 
every 6 months 
NIH Clinical 
Center as 
possible 
Includes physician visit, labs, scans 
and QOL questionnaires. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 13-C-0114 
CONTINUATION: page 3 of 10 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
Birth Control 
If you are a woman who is breast feeding or pregnant, you may not take part in the study because 
we don’t know how this medicine would affect your baby or your unborn child. If you are a 
woman who can become pregnant, or are the partner of a woman who can become pregnant, you 
will need to practice an effective form of birth control before starting study treatment, during 
study treatment, and for 6 months after you finish study treatment.  If you think that you or your 
partner is pregnant, you should tell your study doctor or nurse at once.   
Effective forms of birth control include: 
• abstinence  
• intrauterine device (IUD) 
• hormonal (birth control pills, injections, or implants) 
• tubal ligation 
• vasectomy 
What will happen if you take part in this research study?   
Before you begin the study: 
You will have several tests performed to be certain it is safe for you to have the operation and the 
HIPEC.  This may include blood tests, CT and MRI scans, pulmonary and heart function tests; 
you may also have consultations with a cardiologist and an anesthesiologist. 
Surgery to Remove All of Your Tumors: 
Once you have completed all of 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.  
In order to remove all of the tumors in your abdomen, you will need to have a major operation.  
This will include removing the tumors as well as parts of any organs that the tumors may be 
attached to (for example liver, intestines.) If you have tumors in your peritoneum (the thin film 
of tissue that covers all of your abdominal organs) this will be removed.  After we have removed 
all of the tumors that we can see, you will undergo HIPEC while you are in the operating room.  
If your surgeon cannot remove the majority of your tumors or if the surgeon considers it unsafe 
you will not receive the HIPEC.  
 
 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 13-C-0114 
CONTINUATION: page 4 of 10 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
HIPEC 
Two catheters (or thin tubes) will be put in your abdomen.  The cisplatin will be diluted in a 
heated solution and 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 90 minutes at a temperature of about 104 – 105 
degrees, which is above your normal body temperature.  After your abdomen has been bathed for 
90 minutes, the chemotherapy will be rinsed out and the catheters will be removed.  During this 
procedure we will carefully monitor your 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 second 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 7-14 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 every few 
weeks until you have fully recovered from the operation and HIPEC.   After that, you will be 
seen about every 3 months for the first year; every four months for the next year and then every 
six months thereafter.  If you are not able to come to the NIH Clinical Center, we will contact 
you by phone or e-mail and may ask that you send copies of your scans, lab works and physician 
notes to us.  
Health Related Quality of Life Forms (HRQOL) 
At several points during this study, we will ask you to complete 2 health related quality of life 
questionnaires.  This will take about 15 minutes and we will ask that you complete the 
questionnaires by yourself.  We will ask you to do this before you have your operation and then 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 13-C-0114 
CONTINUATION: page 5 of 10 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
during your follow up visits.  You can decide not to complete the questionnaires at any point and 
this will not affect your treatment.  
Risks or Discomforts of Participation 
What side effects or risks can I expect from being in this study? The operation to remove the 
tumors throughout your abdomen is likely to be quite extensive and will incorporate HIPEC as 
well. The risks from this operation, HIPEC and general anesthesia include:  
Likely 
• Pain  
• Temporary slowing or stopping of bowel function, known as an ileus. This could take 
several days to resolve and may require that the tube in your nose that drains your 
stomach stay in place longer 
• Laboratory studies of the liver, particularly bilirubin may be elevated.  This may be due 
to handling or removing part of the liver during surgery or it may be as a result of the 
cisplatin.  Other lab tests may be elevated as well but these too, will usually not cause any 
symptoms and resolve in a few days.  
• This surgery may also cause changes in your bowel pattern, either constipation or 
diarrhea.  Fluid may develop in your abdomen, known as ascites. This may go away on 
its own, or may need to be drained if it becomes too uncomfortable. 
Less Likely 
• Leakage of bowel contents may occur from an area where the bowel was sewn together 
or from any area of your bowel due to the effects of the chemotherapy, the increased 
temperature during 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.    
• 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 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 13-C-0114 
CONTINUATION: page 6 of 10 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
• 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. 
Rare but serious: 
• Heart failure, lung failure, kidney failure, liver failure, blood clots in your extremities or 
lungs and stroke. This may require treatment in the ICU including need for a breathing 
machine, dialysis, and blood pressure medications. 
• Damage to the various organs of your body which may cause your death. 
Risks: Cisplatin 
Likely – these may be mild to severe 
Less Likely – these may be 
mild to severe 
Rare but Serious 
• 
Thinning of your hair 
• 
Decrease in blood counts including white 
blood cells (which increase the risk of 
infection), red cells (which may cause 
fatigue and weakness) and platelets 
(which increase the risk of bleeding). 
• 
Tiredness, insomnia, muscle aches, 
dizziness 
• 
Changes in taste and smell 
• 
Cough, shortness of breath 
• 
Nausea 
• 
Vomiting  
• 
Hearing loss  
 
• 
Permanent kidney 
damage (requiring 
dialysis) 
 
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 prevent your tumors from 
growing back.  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?  


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 13-C-0114 
CONTINUATION: page 7 of 10 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
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. 
Research Subject’s Rights 
What are the costs of taking part in this study?  
If you choose to take part in the study, the following will apply, in keeping with the NIH policy: 
• 
You will receive study treatment at no charge to you. This may include 
surgery, medicines, laboratory testing, x-rays or scans done at the 
Clinical Center, National Institutes of Health (NIH), or arranged for you 
by the research team to be done outside the Clinical Center, NIH if the 
study related treatment is not available at the NIH.  
• 
There are limited funds available to cover the cost of some tests and 
procedures performed outside the Clinical Center, NIH.  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 Clinical Center, NIH. 
• 
Once you have completed taking part in the study, medical care will no 
longer be provided by the Clinical Center, NIH. 
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: 
• The National Cancer Institute (NCI) and other government agencies, like the Food and 
Drug Administration (FDA), which are involved in keeping research safe for people. 
• National Cancer Institute Institutional Review Board 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 13-C-0114 
CONTINUATION: page 8 of 10 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
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.  
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 you have side effects from the treatment that your doctor thinks are too severe 
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. However, according to FDA guidelines, 
information collected on you up to that point may still be provided to or designated 
representatives. 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 Protocol Review Guide.  You may ask your research 
team for a copy of the Protocol Review Guide or for more information.  Members of the research 
team who do not work for NIH are expected to follow these guidelines but they do not need to 
report their personal finances to the NIH. 
Members of the research team working on this study may have up to $15,000 of stock in the 
companies that make products used in this study.  This is allowed under federal rules and is not a 
conflict of interest.  


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
STUDY NUMBER:13-C-0114 
CONTINUATION: page 9 of 10 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH 
STUDY (Continuation Sheet) 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
 
OTHER PERTINENT INFORMATION 
1. 
Confidentiality.  When results of an NIH research study are reported in medical journals 
or at scientific meetings, the people who take part are not named and identified.  In most cases, 
the NIH will not release any information about your research involvement without your written 
permission.  However, if you sign a release of information form, for example, for an insurance 
company, the NIH will give the insurance company information from your medical record.  This 
information might affect (either favorably or unfavorably) the willingness of the insurance 
company to sell you insurance. 
The Federal Privacy Act protects the confidentiality of your NIH medical records.  However, you 
should know that the Act allows release of some information from your medical record without 
your permission, for example, if it is required by the Food and Drug Administration (FDA), 
members of Congress, law enforcement officials, or authorized hospital accreditation 
organizations. 
2. 
Policy Regarding Research-Related Injuries.  The Clinical Center will provide short-
term medical care for any injury resulting from your participation in research here.  In general, 
no long-term medical care or financial compensation for research-related injuries will be 
provided by the National Institutes of Health, the Clinical Center, or the Federal Government.  
However, you have the right to pursue legal remedy if you believe that your injury justifies such 
action. 
3. 
Payments.  The amount of payment to research volunteers is guided by the National 
Institutes of Health policies.  In general, patients are not paid for taking part in research studies at 
the National Institutes of Health.  Reimbursement of travel and subsistence will be offered 
consistent with NIH guidelines. 
4. 
Problems or Questions.  If you have any problems or questions about this study, or 
about your rights as a research participant, or about any research-related injury, contact the 
Principal Investigator, Jeremy Davis, M.D., Building 10, Room 4-3760, Telephone:  240-760-
6229. You may also call the Clinical Center Patient Representative at 301-496-2626.  
5. 
Consent Document.  Please keep a copy of this document in case you want to read it 
again. 
 
 
 
 
 
 
 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
STUDY NUMBER:13-C-0114 
CONTINUATION: page 10 of 10 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH 
STUDY (Continuation Sheet) 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
 
 
COMPLETE APPROPRIATE ITEM(S) BELOW: 
A. Adult Patient’s Consent 
B. Parent’s Permission for Minor Patient. 
I have read the explanation about this study 
and have been given the opportunity to discuss 
it and to ask questions.  I hereby consent to 
take part in this study. 
I have read the explanation about this study 
and have been given the opportunity to discuss 
it and to ask questions.  I hereby give 
permission for my child to take part in this 
study.   
(Attach NIH 2514-2, Minor’s Assent, if 
applicable.) 
 
  
  
 
 
 
Signature of Adult Patient/ 
Legal Representative 
Date 
Signature of Parent(s)/ Guardian Date 
 
 
Print Name 
 
 
Print Name 
C. Child’s Verbal Assent (If Applicable) 
The information in the above consent was described to my child and my child agrees to 
participate in the study. 
 
  
  
 
Signature of Parent(s)/Guardian 
Date 
Print Name 
THIS CONSENT DOCUMENT HAS BEEN APPROVED FOR USE  
FROM SEPTEMBER 25, 2017 THROUGH SEPTEMBER 24, 2018.  
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
Date 
Signature of Witness 
Date 
 
 
Print Name 
 
 
Print Name