A Phase II Study of Hyperthermic Peritoneal Perfusion (HIPEC) for Adolescent and Young Adults With Desmoplastic Small Round Cell Tumor and Other Non-Carcinomas
Phase: PHASE2
Conditions: Advanced Cancers, Sarcoma
Sponsor: M.D. Anderson Cancer Center

 
2009-0528: A phase II study of hyperthermic peritoneal perfusion (HIPEC) for 
adolescent and young adults with desmoplastic small round cell tumor (DSRCT) and 
other non-carcinomas  
 
 
 
 
 
 
 
 
 
 
Principal Investigator:   
A. Hayes-Jordan, MD 
 
 
 
 
 
 
Co-Investigators:  
 
Paul Mansfield, MD 
 
 
 
 
 
 
Richard Royal, MD 
 
 
 
 
 
 
Keith Fournier, MD 
 
 
 

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Background 
Extensive peritoneal disease or peritoneal carcinomatosis represents an 
aggressive mode of spread for many tumors which ultimately results in death.  In most 
cases progression of the intraperitoneal disease precedes distant metastasis and 
patients typically die of complications related to the intraperitoneal disease. There is 
no standard chemotherapy which has shown promise in the treatment of peritoneal 
carcinomatosis for adults or children. The extent of retroperitoneal disease can limit 
complete surgical resection and the intensive post-operative chemotherapy regimens 
are only useful if a complete response (CR) is evident. For sarcomatosis as is found 
in desmoplastic small round cell tumor (DSRCT), if residual disease is present there 
have been no survivors after intensive chemotherapy even with stem cell rescue. (1) 
This may be related to the difficulty in obtaining cytotoxic concentrations of 
chemotherapy within the tumor parenchyma. A regional approach to treating the 
intraperitoneal tumor is appealing as a means of delivering high concentrations of 
chemotherapeutic agents directly to the tumor while limiting systemic toxicity. (By 
means of using the peritoneal surface as barrier to systemic absorption) (2)  This 
approach has been demonstrated to be very effective for advanced ovarian cancer, 
appendiceal carcinoma and has become the standard care for adults in many cancer 
centers. (3)  In phase I and II clinical trials, this strategy has also been found to 
improve disease free survival in mesothelioma and gastric cancer. (4-6) 
DSRCT primarily presents in children and young adults age 5-30, 90% male, 
with dozens to hundreds of abdominal tumor implants. Less than 200 cases are 
reported in the world literature and therefore treatment options are limited. Despite 
chemotherapy, aggressive tumor debulking and radiotherapy, 3 year survival is 20-
30%. After aggressive tumor debulking of Desmoplastic round cell tumor (DSRCT), 
various strategies have been employed which direct therapy toward the peritoneal 
disease because of the characteristic loco-regional pattern of spread. Such 
approaches have included intraoperative radiation therapy (IORT) and 
hyperfractionated radiation therapy. (7-10) Some chemotherapy and radiation 
responses have been documented, but local abdominal recurrence shortly follows.  
While these approaches attest to the acknowledged importance of controlling intra-
abdominal disease, they have not been uniformly successful in the long term 
complications of secondary tumors. (11-13)   
Other rare pediatric tumors which can recur and metastasize in the abdominal 
cavity include Wilms’ tumor, colon carcinoma, sarcoma, and malignant ovarian germ 
cell tumor. With advanced intraperitoneal disease, these tumors are usually fatal 
despite aggressive chemotherapy and radiation therapy.  In a novel approach to these 
aggressive tumors, here at UT MDACC, an investigator initiated phase I study found 
that continuous hyperthermic peritoneal perfusion, also known as HIPEC, is safe in 
children.   
HIPEC is a technique for combining hyperthermia and chemotherapeutic 
agents delivered intraoperatively to the peritoneal and retroperitoneal surface via a 
recirculating perfusion circuit. (14)  In addition to adult clinical trials, the support for 
this concept comes from in vivo and in vitro laboratory studies.  The selective lethal 
effect of supranormal temperatures on human and murine neoplastic cells has been 
well established in laboratory models. (15-17) A variety of cell lines including colon 
carcinoma and melanoma have been shown to be sensitive to temperatures ranging 
from 42 to 45°C when exposed for a period of 2 to 4 hours while their non-neoplastic 
parental cell types are largely unaffected. In vivo, there appears to be a differential 
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response of normal and tumor microcirculation in response to hyperthermia. (18)  In 
response to hyperthermia, normal tissue will show a dramatic and temperature 
dependent increase in blood flow at temperatures up to 50°C. In contrast, blood flow 
through neoplastic tissue will increase to a much smaller extent and stasis occurs at 
lower temperatures which are well tolerated by normal tissue. Therefore, there 
appears to be two fundamental mechanisms by which supranormal temperatures can 
be selectively toxic to neoplastic cells via both direct cytotoxic effects and vascular 
stasis. 
As mentioned, for drugs administered into the peritoneal cavity, the 
simultaneous systemic administration of neutralizing agents can provide protection 
against the systemic toxic effects of drug which leaks into the circulation. Systemic 
sodium thiosulfate has been shown to covalently bind and inactivate cisplatin in the 
systemic circulation and obviate the expected renal toxicities. The use of sodium 
thiosulfate allows the administration of high doses of intraperitoneal cisplatin which 
might result in blood levels comparable to an intravenous administration of drug. (19)  
A loading dose of sodium thiosulfate, followed by continuous infusion has completely 
prevented any substantial rise in serum creatinine with doses of cisplatin up to 270 
mg/M2 administered intraperitoneally with a 4-hour dwell time. 
The major disadvantage of intraperitoneal drug administration appears to be 
that drug uptake by tumor tissue is mostly through capillary diffusion rather than 
capillary flow. With cisplatin in a normothermic environment, tumor penetration up to 3 
mm has been shown. This would theoretically be adequate to penetrate a tumor 
deposit 6 mm in diameter. Thus it is clear that aggressive surgical debulking, leaving 
minimal gross residual disease, will be optimal for the maximum therapeutic effect 
with cisplatin.   
In adult studies of carcinomatosis, there were no procedure related mortalities; 
morbidity included renal impairment, ascites, and pancreatitis. Dose limiting toxicity 
included grade III leukopenia, grade IV neutropenia and grade III and IV 
thrombocytopenia at the higher doses only (greater than 800 mg/M2). (20, 21)  
Specifically, no patient had a prolonged postoperative ileus and no adverse effect on 
wound healing was observed. Following surgery, the median time before tolerating 
enteral feeds was 5 days (range 1-7 days), and patients could tolerate a regular diet 
at a median of 7 days (range 4-8 days). Neither patient who had undergone bowel 
resection and anastamosis followed by HIPEC had any anastamotic complication. 
One patient suffered a subfascial hematoma incurred from trauma to the left inferior 
epigastric artery. (20) In the mesothelioma study, the MTD of cisplatin was 300 
mg/M2. Above this dose there were significant rises in creatinine and one patient 
required temporary hemodialysis. (21)  There have not been any untoward effects of 
the HIPEC on the ability of these patients to heal incisional wounds and convalesce 
uneventfully.  
This intraoperative treatment using HIPEC in children has provided some very 
encouraging results. The phase I study of HIPEC in children done here (protocol 
#2005-0917) proved to be safe. There were no protocol related deaths.  Two SAE’s 
included temporary cardiomyopathy likely related to the 4 kg+ tumor resected and 
supraventricular tachycardia likely related to central venous catheter malposition. 
Several children had temporary increased creatinine, up to 1.9. However, no 
problems were seen with urinary output; serum creatinine returned to normal within 1-
2 weeks without treatment or dialysis.  
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Preliminary results suggest 3 year disease free survival is 71% (compared to 
26% in historic controls) and disease free interval is increased 5 times from 1.6 to 9 
months in the subset of patients with DSRCT. The 2 sarcoma patients died within 6 
months and one mesothelioma patient is alive with minimal disease. Another 
mesothelioma patient in 3rd relapse was treated with surgery + HIPEC is >2 years 
from surgery. In summary there appears to be benefit in many and we have reached a 
dose limiting toxicity (DLT), elevated creatinine using HIPEC with cisplatin at 150 
mg/M2.  
   
Rationale 
Desmoplastic small round cell tumor (DSRCT) is a rare disease of children, 
adolescents and young adults, which begins in the abdominal cavity.  Less than 200 
cases are reported in the world literature.  The primary organ of DSRCT origin is the 
peritoneum.  It is a very unique tumor that is difficult to treat because of the infiltrative 
and diffuse nature of the peritoneum.  Patients may present with dozens to hundreds 
of tumors studding the peritoneal cavity.  DSRCT was only recently described in 1991 
and since then multimodality treatment including chemotherapy, radiation and 
aggressive surgery, has not improved outcome.  Here at UT MDACC the PI has 
conducted a phase I trial in children with 'carcinomatosis' who underwent continuous 
hyperthermic peritoneal perfusion using cisplatin after cytoreductive surgery. (This 
was an investigator initiated trial and we were the only center in the North America 
embarking on this effort)  
 
For continuity, we propose to open the phase II study on the subset of patients 
with the best prognosis after HIPEC, those with DSRCT. In data not yet published, we 
compared the 9 patients with DSRCT who have undergone HIPEC with 15 historical 
adolescent and adult patients with DSRCT at UT MDACC who had chemotherapy +/- 
radiation therapy only and no HIPEC and found a survival advantage of 41 weeks in 
the patients undergoing HIPEC, a 3 year median survival of 26% for those not 
undergoing HIPEC and 71% for those who had HIPEC. This is very preliminary data 
with few patients and follow up is only 1-3 years. Further study of HIPEC in DSRCT is 
warranted. The surgical study plan and delivery of hyperthermic chemotherapy are 
the same as the previously approved phase I protocol. The maximum tolerated dose, 
the safe dose of cisplatin found in phase I, is 100 mg/M
2. Pediatric and adult patients 
with other non-carcinoma tumors with extensive peritoneal disease will be eligible if 
no standard HIPEC treatment has been established for these patients. Results of the 
research analysis will not be shared with the patient during the conduct of this study 
nor will the results influence the clinical strategy.  
 
 
1.0      Primary objectives of the study 
Primary objective 1:  To determine the efficacy of HIPEC using hyperthermic 
cisplatin given as a continuous perfusion after complete abdominal tumor excision in 
patients with DSRCT. 
   
Primary objective 2:  To determine the morbidity of extensive tumor resection 
and HIPEC on patients with DSRCT and other non-carcinoma tumors with extensive 
abdominal disease. 
 
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Methods and Research Plan 
The current study is designed to evaluate the efficacy of HIPEC with cisplatin, in 
children adolescents and young adults with disseminated intra-peritoneal disease. 
This phase II pilot study will include aggressive surgical debulking, in patients with 
abdominal desmoplastic small round cell tumor.   
 
2.0 
ELIGIBILITY ASSESSMENT AND ENROLLMENT 
 
2.1 
Inclusion Criteria 
 
2.1.1 Age greater than or equal to 1 year. 
 
2.1.2 Histologically or genetically proven diffuse peritoneal or 
retroperitoneal tumor from desmoplastic round cell tumor, 
ovarian germ cell, sarcoma, Wilms’ tumor, or other non-
carcinoma tumors. 
 
2.1.3 Radiologic workup must demonstrate that the disease is 
confined to the abdominal cavity 
 
2.1.4 Radiologic workup or prior abdominal exploration must be 
consistent with disease which can be debulked to a 
residual size of less than or equal to 1 cm thickness per 
tumor deposit 
 
2.1.5 Patients must have a minimum expected duration of 
survival of greater than 6 weeks as determined and 
documented by the attending surgeon or medical 
oncologist. 
 
2.1.6 Patients must not have any systemic illness which 
precludes them from being an operative candidate as 
determined by anesthesia preoperative evaluation.  This 
includes but is not limited to, sepsis, liver failure, pregnant 
or lactating females. 
 
2.1.7 Patients must have fully intact mental status and normal 
neurologic abilities. Intact mental status is defined by ‘the 
capacity to identify and recall one's identity and place in 
time and space.’ Assessment of mental status and 
documentation of fully intact mental status will be 
completed using physical and mental exam by the 
referring doctor or oncologist.   
 
2.1.8 Patients must have adequate renal function (serum 
creatinine < 1.5 mg/dl without history dialysis or renal 
failure or creatinine clearance less than 50 mL/min/1.73 M2 
if less than 5 years of age)  
 
2.1.9 Patients will be eligible if the WBC is >2000/µl or ANC is 
>1,500 and platelets are > 100,000/mm3 
 
2.1.10 Patients will be eligible if serum total bilirubin and liver 
enzymes are < 2 times the upper limit of normal 
 
2.1.11 Patients must be recovered from any toxicity from all prior 
chemotherapy, immunotherapy, or radiotherapy and be at 
least 14 days past the date of their last treatment 
 
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2.2 
Exclusion criteria 
 
2.2.1 Patients will be ineligible if they have any concomitant 
cardiopulmonary disease which would place them at 
unacceptable risk for a major surgical procedure 
 
2.2.2 Patients will be ineligible if they have disease outside of 
the abdominal cavity which is uncontrolled 
 
2.2.3 Patients will be ineligible if they have a baseline neurologic 
toxicity of Grade 3 or greater (because of the potential 
neurotoxicity associated with platinum) 
 
2.2.4 Patients who have failed previous intraperitoneal platinum 
therapy will be ineligible (“Failed” is having disease 
recurrence < 3 months.) 
 
2.2.5 Patients with Retroperitoneal Liposarcoma will be ineligible 
 
 
2.3 
Research Eligibility Evaluation 
 
2.3.1 A complete history and physical examination 
 
2.3.2 Chest, abdomen and pelvic CT scan or MRI within 3 
weeks of study entry 
 
2.3.3 Blood tests including, CBC, PT/PTT, sodium, potassium, 
chloride, carbon dioxide, BUN, creatinine, calcium, 
amylase, magnesium, phosphorus, AST, ALT, total 
bilirubin, alkaline phosphatase, albumin within one week of 
study entry 
 
2.3.4 Bone scan and brain MRI as clinically indicated within two 
weeks of study entry 
 
2.3.5 Echocardiogram and ECG required within two weeks of 
study entry  
 
2.3.6 Review of pathology slides of tumor specimen obtained 
from biopsy or surgical resection, by MDACC pathologist 
(unless genetic confirmation is previously obtained) 
 
2.3.7 Urine pregnancy test will be required per institutional 
pregnancy assessment. (Policy no. CLN1114) 
 
2.3.8 Audiology evaluation will be done before beginning 
therapy as a baseline 
 
2.3.9    Patients under 5 years of age must have a 24 hour urine 
collection for creatinine clearance. The value obtained 
from the lab at MDACC will be multiplied by 1.73 and 
divided by the patients BSA to obtain the corrected 
creatinine clearance in the units mL/min/1.73 M2 
 
 
3.0 
Study Implementation: Surgery 
 
3.1 
Procedures and therapeutic agents 
 
3.1.1 Each operation will be carefully planned and informed 
consent obtained from the patient 18 or older or the 
parents (and assent from child if age appropriate) after a 
detailed discussion of possible complications, risks and 
possible benefits.   
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3.1.2 A general anesthetic is administered and the patient is 
placed on a cooling blanket that will initially not be turned 
on).  Esophageal and bladder temperature probes will be 
inserted.  Unless already in place upon arrival to the OR; a 
central venous catheter, large bore IV’s and an arterial line 
will be placed.  An exploratory laparotomy will be 
performed.  If the surgeon determines the operation to be 
feasible and safe, a debulking operation will be performed 
which will include all disease possible, leaving tumor 
nodules no greater than 1 cm thick. If the surgeon 
determines that the patient cannot be cytoreduced leaving 
no tumor nodules in aggregate greater than 1 cm, patients 
will not receive HIPEC. These patients may then receive 
surgical debulking but will not be eligible to be enrolled on 
this protocol.  The extent of the operation will vary 
depending on the tumor.  Possible procedures include 
partial liver resection, partial, limited pancreatic resection, 
splenectomy, or bowel resection. Non-surgical ablation of 
liver tumors is acceptable.   
 
3.1.3 HIPEC- After cytoreductive surgery and lysis of adhesions, 
two large bore catheters are placed in the peritoneal cavity 
through the incision. The first is placed over the dome of 
the liver for perfusion influx and a second catheter is 
placed so that the tip lies in the pelvis for perfusion efflux. 
Up to eight temperature probes are placed beneath the 
peritoneal surface or at the influx and efflux catheters. The 
abdominal incision is closed and HIPEC is performed.  
 
3.1.4 HIPEC and Cisplatin- Thirty minutes before HIPEC is 
begun, body temperature is cooled to 35°C. During the 
procedure, the cooling blanket and ice packs at the 
patients head and legs will be adjusted as necessary to 
maintain core body temperature below 38.5°C (as 
measured by esophageal probe). The catheters are 
connected to a perfusion circuit. The perfusate passes 
from a reservoir through a roller pump, heat exchanger 
and then into the abdominal cavity. Efflux from a second 
catheter is then recirculated through the reservoir and 
pump. The perfusion flow rate will be maintained to distend 
the abdomen 5 (+2) liters/minute, and a perfusate volume 
will be maintained which moderately distends the 
abdominal cavity.  Before the instillation of Cisplatin, the 
peritoneal cavity is warmed to a target of 40°C (+1°C) as 
estimated by the influx/efflux catheter or peritoneal probe 
and the anesthesiologist will hydrate the patient with 
isotonic solution.  The perfusion is continued for 90 
minutes after adding the cisplatin. Cisplatin at 100 mg/M2 
(1mg/1mL concentration in syringes) is to be added to the 
perfusate. The total maximum dose will not exceed  
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                                                                      130 mg. Constant physical manipulation of the abdomen is 
maintained for the entire 90 minutes to assure even 
distribution of the perfusate. Peritoneal temperature is 
measured every 10-15 minutes by up to eight probes 
placed either beneath the peritoneal surface or at the influx 
and efflux catheters. At the end of the perfusion, the 
abdomen is re-opened and the perfusate is again irrigated 
from the abdominal cavity. The bowel is then thoroughly 
re-inspected for any perforations incurred and bowel 
anastamosis are completed. Throughout the procedure 
urine output must be maintained at 1-2 cc/kg/hr. Post-
operative hydration will include 1.5 x maintenance normal 
saline or lactating ringer and maintenance of urine output 
of at least 1cc/kg/hr and replacing urine output cc/cc every 
hour with normal saline, for the first 48 hours to prevent 
hypovolemia and renal failure. 
 
3.1.5 Retroperitoneal tumors- In the case of a retroperitoneal 
tumor, after tumor debulking, exposure of the entire 
retroperitoneum in the area of the tumor bed, will be 
maintained. The remainder of the procedure will be the 
same as above.  Stable perfusion parameters are obtained 
and the peritoneal cavity is warmed to a minimum of 40°C 
(+1°C), prior to adding the cisplatin. The perfusion is 
continued for 90 minutes after adding the cisplatin. At the 
end of the perfusion the perfusate is irrigated from the 
abdominal cavity and the abdominal wall is closed in the 
usual fashion.   
 
3.1.6 Sodium thiosulfate- In order to limit the systemic toxicity of 
cisplatin, sodium thiosulfate will be administered by 
loading dose and then a 12 hour continuous intravenous 
infusion. A loading dose of 7.5 gm/M2 (maximum 12.5 gm) 
of sodium thiosulfate will be diluted in 20 ml/kg of 0.9% 
normal saline up to 500 mL. This loading dose will be 
infused over 20 minutes beginning 30 minutes (+ 15 
minutes) after the addition of cisplatin to the peritoneal 
perfusion circuit. Then maintenance infusion of sodium 
thiosulfate 1.275 gm/M2/hr for 12 hours will be delivered by 
infusion pump  
 
 
4.0 
Data Collection and Evaluation 
 
4.1 
Data Collection   
All patients will be entered in PDMS/CORe with fields to reflect 
the information on the data collection forms included in Appendix 
1.   
 
 
 
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4.2 
Response Criteria and Statistical Considerations 
 
4.2.1 This is a phase II study of continuous hyperthermia 
peritoneal perfusion (HIPEC) in patients with desmoplastic 
round cell tumor (DSRCT) and non-DSRCT patients. The 
primary objective is to assess the efficacy of this 
treatment, with a primary endpoint of time to relapse. The 
historical median time to relapse for DSRCT patients 
without HIPEC treatment was about 1.6 months. A 
maximum of 22 patients will be enrolled in MDACC at an 
estimated accrual rate of 1 patient every 2 months 
including a total of 5 non-DSRCT patients. Patients will be 
followed up until relapse, death or for 6 months after the 
treatment, which ever occur first. It would be encouraging 
if the median time to relapse could increase to 3.2 months 
with the HIPEC treatment. The toxicity and efficacy will be 
monitored during the study, and all the data will be used to 
update the prior distributions for toxicity and efficacy 
parameters. The study will be stopped for toxicity and 
futility based on the following stopping rules.   
 
4.2.2 The primary endpoint TTP will be monitored using the 
method of Thall et al. (23). Denote median (TTP) = mH for 
patients without HIPEC treatment and mE for patients with 
HIPEC treatment. We assume that TTP is distributed 
exponentially with mean of mH and mE, respectively, in 
patients without and with HIPEC treatment.  Under a 
Bayesian model, we will further assume that mH has an 
inverse gamma (IG) prior with parameters (16.2, 24.3), 
with a mean of median TTP=1.6 months and variance = 
0.18. We also assume that mE follows IG prior (2.03, 1.64) 
with the same median TTP as mH but with a much larger 
variance (100) to reflect much greater uncertainty about 
TTP in patients with HIPEC treatment. The TTP data will 
be monitored continuously, and the study will be 
terminated early if Pr (mH + d < mE | data) < 0.05, where d= 
1.6 month. Specifically, the trial will be stopped early if, 
given the current data, there is less than 5% chance that 
the median TTP will improve by more than 1.6 month in 
patients treated with HIPEC, compared to those without 
HIPEC treatment. The operating characteristics of this 
decision rule are summarized in Table 1. 
 
4.2.3 In addition, toxicity will be monitored closely in all patients. 
The evaluation of the toxicity data will begin after 
enrollment of 8 patients. Denote the probability of toxicity 
by θE, where toxicity is defined as any Grade 3 or greater 
renal, cardiac, respiratory or Grade 4 hematologic 
complications attributable to HIPEC.  We assume θE ~ 
beta (0.6, 1.4).  Our stopping rule is given by the following 
probability statement: Pr (θE > 0.30 | data) >0.8. That is,  
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                                                                      we will stop the trial if, at any time during the study, we 
determine that there is more than 80% chance that the 
toxicity rate is more than 30%. Stopping boundaries 
corresponding to this stopping rule are to terminate the 
trial if (# Grade 3 or greater renal, cardiac, respiratory or 
Grade 4 hematologic complications) / (# patients 
evaluated) ≥4/8, 5/9, 6/12, 7/15, 8/18. That is, the trial will 
be stopped if 4 or more patients out of 8 patients, 5 or 
more patients out of 9 patients, and 6 or more patients out 
of 10, 11 and 12 patients, 7 or more patients out of 13, 14 
and 15 patients, 8 or more patients out of 16, 17, 18 
patients experience toxicity. Please note that for the first 8 
patients, if 4 or more out of 4-7 patients experience 
toxicity, the trial will also be stopped, because the stopping 
boundary is already passed. The operating characteristics 
are summarized in Table 2. 
4.2.4 Analysis Plan: For discrete or categorical data, descriptive 
statistics will include tabulations of frequencies. For 
continuous data, summary statistics including n, mean, 
standard deviation, median, minimum and maximum will 
be computed. The median time to progression and its 95% 
confidence interval will be estimated.  Kaplan-Meier 
method, Log rank test and Cox proportional hazards 
regression modeling will be utilized to analyze time to 
progression and overall survival. The study will use 
Department of Biostatistics Clinical Trial Conduct website 
to conduct/monitor with regard to the defined Bayesian 
rules.  
 
Table 1. Operating characteristics for the design 
True median 
Time to 
progression 
(month) 
Pr(stop early) 
Average Number of 
Patients Treated 
(25th, 75th 
percentiles) 
 1 
        0.998 
        4 (1,5) 
 1.6 
        0.775 
        9 (2,18) 
 3.2 
        0.178 
      17 (2,20) 
4 
        0.126 
      18 (20,20) 
 
Table 2. 
 
 
 
 
 
 
 
 
True toxicity rate 
Early Stopping Probability 
0.1  
               0.006 
0.2  
               0.094 
0.3  
                0.344 
0.4  
                0.665 
0.5  
                0.897 
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                                                      4.3 
Pathologic response criteria 
 
4.3.1 At the completion of cytoreductive surgery, one 1cm  
 
 
nodule will remain in the peritoneal cavity during the  
 
 
perfusion procedure. 
 
  
 One nodule of  
tumor removed before hyperthermic perfusion 
treatment will be preserved  for comparison. Tumor 
nodules will be divided in three portions and 
preserved in paraffin, a frozen block and as snap  
frozen tissue. Slides will then be cut and then used 
for immunohistochemical analysis of apoptosis, 
 proliferation and autophagy.  
4.3.2    Snap frozen tissue will be used for RNA extraction 
           and gene expression profiling for the purpose of 
           categorizing patient tumors based on response to  
           hyperthermic peritoneal perfusion treatment. The  
           Illumina platform will be used. A comparison of 6 
 patient samples, pre and post treatment, for a total of 
          12 samples will be analyzed. We will create a log of 
          response comparing pre and post treatment gene 
          expression and identify gene signatures for pathologic 
          vs. non pathologic responders. Paraffin embedded 
          samples will be used for tissue microarray, comparing 
          pre and post treatment, to validate gene expression 
          data at the protein level using IHC. Upon completion 
          of full analysis, the tissue samples will be destroyed.               
4.3.3   This information will be critical in the future in that it 
          will allow the treating physician to identify which 
          DSRCT patients would best respond to hyperthermic 
          peritoneal perfusion cisplatin treatment by genetic 
          tumor characteristics. (Dr. Alexander Lazar,  
          pathologist, is part of the sarcoma center under the  
          direction of Dr. Lev) 
 
 
4.4 
Re treatment criteria 
 
4.4.1 If patients return with recurrent measurable disease and 
experienced a 6 month disease free interval since the last 
HIPEC, they will be offered a reperfusion when there is 
radiographic evidence of recurrent intra-abdominal disease 
and no new contraindications.  Patients having a 
reperfusion will be treated with 50 mg/M2 of cisplatin. (This 
is based on renal insufficiency seen in 2 patients who 
underwent 2 perfusions at 100 mg/M2)  
 
4.4.2 Patients who progress will be offered other treatment 
alternatives 
 
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4.5 
On study evaluation 
 
4.5.1 Patients will undergo laboratory tests, imaging and 
physical exam as per on study criteria.    
 
4.5.2 During HIPEC patients will have continuous core 
temperature monitoring by the esophageal probe and 
bladder probe.  Peritoneal temperature is measured every 
10-15 minutes by up to eight probes placed either beneath 
the peritoneal surface or at the influx and efflux catheters. 
If the temperatures are increasing above 40°C (+1), the 
temperature of the perfusate will be reduced. If the 
temperature readings are too low, the emphasis of the 
manual agitation will be redirected to that area of the 
abdomen.   
 
4.5.3 Patients will be followed postoperatively with daily CBC, 
sodium, potassium, chloride, carbon dioxide, BUN, 
creatinine, AST, ALT, calcium, albumin, magnesium, 
phosphorous, total bilirubin, alkaline phosphatase, 
amylase for 5 +/-2 days and then twice weekly until 
discharge; and post-discharge at day 14+/-3 days and day 
30+/- 3 days and at 3 and 6 month (+/-2 weeks) follow-up 
(Appendix 1) Adverse events will be assessed on the 
same timetable. 
 
4.5.4 Patients will be monitored in the PICU no less than 48 
hours. If necessary, adult patients will be admitted to ICU. 
 
4.5.5 Evaluation of measurable disease will be performed one 
month, 3 months and 6 months postoperatively (+/- 2 
weeks) using CT or MRI and physical exam. (CT or MRI 
scan performed only at 3 and 6 months) 
 
4.5.6 Audiology evaluation will also be performed at one month 
evaluation. 
 
 
4.6 
Concurrent Therapies 
 
4.6.1 Patients will be allowed to proceed with any post-operative 
chemotherapy including allogeneic or autologous bone 
marrow transplantation. No concurrent medications will be 
given at the time of study drug administration since this is 
only a 90 minute period in the operating room. However, 
baseline medications and all medications through the 30 
days follow up will be entered into PDMS/CORe.   
 
 
4.7 
Pharmacokinetics (Optional) 
 
4.7.1 Blood and peritoneal fluid samples (2.0 ml) will be 
collected in purple top tubes, centrifuged, and supernatant 
or plasma collected and stored at -20°C until analyzed. 
 
4.7.2 Blood and peritoneal fluid will be collected prior to the start 
of cisplatin-HIPEC and then at times 0, 30, 60 and 90  
 
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                                                                                                              14 Nov. 2013 
 
                                                                      minutes. An additional blood sample will be collected 24 
hours (+/- 8 hours) after the start of HIPEC. 
 
4.7.3 Platinum levels in plasma and perfusate will be determined 
by the laboratory. 
 
4.7.4 Pharmacokinetic profiles of cisplatin in plasma and 
perfusate will be determined and compared.   
 
 
4.8 
Off Study Criteria 
 
4.8.1 Progression of disease- Once patients demonstrate 
progression of disease at follow up MRI or CT or PET-CT 
scans at 3 or 6 months, other therapies may be offered 
(but are not considered part of this study). Disease 
progression is defined by radiographically visible nodules 
greater than 1.5 cm. However, patients would be followed 
until death even after the 6 month follow-up by notification 
by primary oncologist.   
 
4.8.2 Voluntary withdrawal 
 
4.8.3 Non-compliance with follow-up scheme 
 
4.8.4 At the time of cytoreductive surgery if patients are found to 
have disease which cannot be debulked to a diameter <1 
cm in aggregate will be taken off study and not given the 
perfusion treatment.  
  
4.9       Serious Adverse Event Reporting (SAE) 
An adverse event or suspected adverse reaction is considered “serious”   
if, in the view of either the investigator or the sponsor, it results in any of         
the following outcomes: 
• Death 
• A life-threatening adverse drug experience – any adverse experience that 
places the patient, in the view of the initial reporter, at immediate risk of 
death from the adverse experience as it occurred. It does not include an 
adverse experience that, had it occurred in a more severe form, might have 
caused death. 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A 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. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse 
(21 CFR 312.32). 
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                                                                                                              14 Nov. 2013 
 
• Important medical events as defined above may also be considered 
serious adverse events. Any important medical event can and should 
be reported as an SAE if deemed appropriate by the Principal 
Investigator or the IRB. 
• All events occurring during the conduct of a protocol and meeting the 
definition of a SAE must be reported to the IRB in accordance with the 
timeframes and procedures outlined in "University of Texas M. D. Anderson 
Cancer Center Institutional Review Board Policy on Reporting Serious 
Adverse Events".  Unless stated otherwise in the protocol, all SAEs, 
expected or unexpected, must be reported to the IRB, regardless of 
attribution (within 5 working days of knowledge of the event). 
• All life-threatening or fatal events, that are unexpected, and related to the 
study drug, must have a written report submitted within 24 hours (next 
working day) of knowledge of the event to the IRB.   
• The MDACC "Internal SAE Report Form for Prompt Reporting" will be 
used for reporting to the IRB.  
• Serious adverse events will be captured from the time the patient 
signs consent until 30 days after the last dose of drug. Serious 
adverse events must be followed until clinical recovery is complete 
and laboratory tests have returned to baseline, progression of the 
event has stabilized, or there has been acceptable resolution of the 
event. 
• Additionally, any serious adverse events that occur after the 30 day 
time period that are related to the study treatment must be reported to 
the IRB. This may include the development of a secondary 
malignancy. 
 
Reporting to FDA: 
• Serious adverse events will be forwarded to FDA by the IRB according to 21 
CFR 312.32. 
 
It is the responsibility of the PI and the research team to ensure serious adverse 
events are reported according to the Code of Federal Regulations, Good 
Clinical Practices, the protocol guidelines, the sponsor’s guidelines, and 
Institutional Review Board policy. 
         
 
 
 
 
 
 
 
 
 
                    
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                                                                                                              14 Nov. 2013 
The PI is responsible for ADR reporting. Adverse events will be documented 
according to the recommended adverse event recording guidelines for Phase II 
protocols as seen below. 
 
Recommended Adverse Event Recording Guidelines  
Attribution 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
  
  
  
  
  
Unrelated Phase I 
Phase I 
Phase I 
Phase II   
Phase I 
Phase II  
Phase III 
Phase I 
Phase II   
Phase III 
Unlikely 
Phase I 
Phase I 
Phase I 
Phase II   
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Possible 
Phase I 
Phase II 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Probable 
Phase I 
Phase II 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Definitive 
Phase I 
Phase II 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
 
 
5.0 
Human Subjects Protection 
 
5.1 
Rationale for use in children- Presently there is no standard 
treatment in children for tumors limited to peritoneal or 
retroperitoneal metastasis. In combination with other intravenous 
agents cisplatin has shown activity against various refractory, 
solid, pediatric tumors.  In the treatment of many recurrent solid 
tumors, cisplatin is utilized as part of the intravenous regimen.  Its 
use in HIPEC in adults has been promising. The PI has 
experience with this procedure in children and is the only one 
who will be performing the HIPEC procedure.  
 
 
5.2 
Informed Consent Benefits, Risks, Discomforts and Alternatives 
 
5.2.1 Consent and Assent -- The investigational nature and 
objectives of this trial, the procedures involved and the 
attendant risks, discomforts, potential benefits and 
potential alternative therapies will be carefully explained to 
the adult patient (>/=18 year old) or to the parent and 
when appropriate, the child, prior to treatment and prior to 
obtaining a signed informed consent as well as assent 
from the child. These discussions will take place in the 
clinic setting as well as the hospital. During the initial 
consultation, the parents are presented a forthright and 
detailed overview of the experimental nature of the 
procedure, its theoretical advantages and disadvantages 
Page 15 of 21 
 

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                                                                                                              14 Nov. 2013 
and an overview of the operative procedure and 
anticipated convalescence. The fact that the patient must 
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 adult patient (>/=18 year old) and/or parents will be 
informed that this therapy could make the patient or the 
child extremely ill and the risks of experiencing short or 
long term adverse effects from this treatment are high. The 
adult patient (>/=18 year old) and/or family is asked to 
review the informed consent document, encouraged to 
make notes, and a follow up discussion is scheduled either 
by phone or in person with the physician or nurse 
investigator and any additional questions will be answered 
prior to considering treatment on this protocol. At the time 
of consent and again the day of surgery, the family is 
reassured that participation in the trial is entirely voluntary 
and that they can withdraw or decide against treatment at 
any time without adverse consequences. Signed consent 
will be verified by the surgeon responsible for the care of 
the patient.  A child life advocate will be a part of the 
informed consent process when the patient is a child.   
 
5.2.2 Risks and Benefits- The potential benefit to a patient 
undergoing this therapy would be palliation in terms of 
preventing or delaying intra-abdominal tumor progression, 
which can be a devastating and painful source of 
symptoms and cause for demise. In addition, significant 
tumor response may extend survival. The risks of this 
protocol include those inherent to extensive abdominal 
surgery. This includes postoperative bleeding, wound 
infection, intra-abdominal abscess, wound dehiscence, 
enterocutaneous fistula, anesthetic complications and 
postoperative death. Also, toxicities of cisplatin therapy 
place the patient at risk. In addition, in the case of intra-
abdominal catastrophe, patients may require re-operation.   
 
5.2.3 Alternatives - Children dying of extensive peritoneal, 
retroperitoneal disease, or carcinomatosis, suffer with 
recurrent bowel obstructions, nausea, vomiting, abdominal 
pain, inability to pass stool, poor appetite and in late 
stages refractory ascites. Because there is presently no 
other treatment alternatives offered in this clinical scenario, 
aggressive treatment as a means of palliation and survival 
benefit, are justified.  There have been many phase I and 
II trials in adults in which long term remissions after HIPEC 
in patients who were otherwise terminal, have been 
realized. Patients will be informed of other experimental 
chemotherapy options available. 
 
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                                                                                                              14 Nov. 2013 
 
6.0 
Pharmaceutical Information 
 
6.1 
Cisplatin (cisplatin) 
 
6.1.1 General 
Cisplatin will be purchased from the Pharmacy for the use 
in this trial. Commercial supply of FDA approved Cisplatin 
will be used. For drug information: Cisplatin Aqueous 
formulation 1mg/ml concentration (Various Vendors). Lot 
numbers will be tracked per drug accountability 
requirements. It will be purchased by an institutional grant 
for this protocol. 
 
6.1.2 Stability and Storage 
Cisplatin is stable at controlled room temperature 15° - 
25°C protected from light and 7 days under fluorescent 
room light. Further dilution at 0.05 or 0.5 mg/mL with 0.9% 
sodium chlorine injection (NS), USP, yields a solution that 
is stable for at least 24 Hours at room temperature. Intact 
vials in reconstituted solution should be maintained at 
room temperature. Do not refrigerate and protect 
unopened container from light. 
 
6.1.3 Preparation 
The total dose of cisplatin will be injected into a bag of 
0.9% sodium chloride for injection, USP, to make 500 mL 
of final volume (+ 10%) prior to administration. 
 
6.1.4 Administration 
Cisplatin 100 mg/M2 {up to 130 mg/M2 maximum dose} (in 
500 mL) will be added to a stable perfusion system. 
 
6.1.5 Toxicities 
Cisplatin produces renal tubular toxicity’s associated with 
renal insufficiency and electrolyte, (i.e. magnesium, 
potassium, calcium, phosphate, carbon dioxide) wasting 
which may result in significant hypomagnesaemia and 
hypokalemia. Neurotoxicity manifests as both sensory and 
motor peripheral neuropathies. Cisplatin is also toxic to the 
8th cranial nerve producing ototoxicity which consists of 
primarily deficits in high frequency auditory acuity, but may 
include vestibular abnormalities. Systemic administration 
of cisplatin at doses similar to those planned in this study 
is associated with significant nausea and     
thrombocytopenia. Transient moderate elevations of 
hepatic transaminases and acute systemic allergic 
reaction including anaphylaxis may also occur. The prior 
phase I study of HIPEC with heated cisplatin has not 
identified any regional intraperitoneal toxicity from cisplatin 
and the dose to be used is 100 mg/M2. The heat may 
cause a prolonged gastroparesis. 
 
 
 
Page 17 of 21 
 

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6.2 
Sodium Thiosulfate 
 
6.2.1 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.   
 
 
6.2.2 Stability and Storage 
Manufacturer’s expiration date is present on the 
commercial formulation.   
 
 
6.2.3 Preparation 
A loading dose of 7.5 gm/M2 (maximum 12.5 gm) of 
sodium thiosulfate will be diluted in 20 mL/kg of 0.9% 
normal saline up to 500 mL. An additional dose of sodium 
thiosulfate 1.275 gm/M2/hr for 12 hours will be diluted in 
0.9% normal saline for maintenance infusion.   
 
 
6.2.4 Administration 
 
 
Sodium thiosulfate will be administered by a loading dose 
and then a 12 hour continuous intravenous infusion.  A 
loading dose of 7.5 gm/M2 (maximum 12.5 gm) of sodium 
thiosulfate will be diluted in 20 mL/kg of 0.9% normal 
saline up to 500 mL. This loading dose will be infused over 
20 minutes beginning 30 minutes (+ 15 minutes) after the 
addition of cisplatin to the peritoneal perfusion circuit. Then 
maintenance infusion of sodium thiosulfate 1.275 gm/ 
M2/hr for 12 hours will be delivered by infusion pump.  
 
 
6.2.5 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 intravenous administration of sodium 
thiosulfate has produced hypokalemia presumably due to 
an osmotic diuretic effect.   
 
 
 
 
 
 
 
 
 
 
Page 18 of 21 
 

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                                                                                                              14 Nov. 2013 
 
Appendix 1 
                                     Clinical and Laboratory Follow up 
 Eval. 
days 
Baseline 
(Pre-op) 
D1      
 
D2 
D3 
D4 
D5 D11 D14 D30 3mo 6mo 
Labs/ 
Tests 
 
 
 
 
 
 
 
 
 
 
 
 
Hb 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hct 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Plt 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Na 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
K 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Cl 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CO2 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BUN 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Cr  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Mg++ 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Ca++ 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Alb 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PO4 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AST 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ALT 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Alk 
Phos 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PT/PTT  
X 
 
 
 
 
 
 
 
 
 
 
TB 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Amy 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PE 
 X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG 
 
X 
 
 
 
 
 
 
 
  
 
Echo 
 
X 
 
 
 
 
 
 
 
  
 
CT scan  
X* 
 
 
 
 
 
 
 
 X 
X 
MRI 
 
X* 
 
 
 
 
 
 
 
 X 
X 
Audio 
 
X 
 
 
 
 
 
 
 
X 
 
 
AE 
 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PK 
 
 X 
 
 
 
 
 
 
 
 
 
Preg. 
 
X  
 
 
 
 
 
 
 
 
 
24-hr 
UCr 
 
X**  
 
 
 
 
 
 
 
 
 
*Choose one or both as clinically indicated. May include PET-CT. TB=total bilirubin, Audio=audiology, 
AE adverse events evaluation, PK= pharmacokinetic cisplatin level at 24 hours, Preg.=pregnancy test 
(blood or urine), Alb=Albumin, D=post op day 
**24 hour urine collection for creatinine clearance calculation for children <5 years old 
 
Optional PK Testing 
0 (pre-perfusion) 
30 min 
60 min 
90 min 
24-hr (post-op) 
Blood 
X 
X 
X 
X 
X 
Peritoneal Fluid 
X 
X 
X 
X 
X 
 
 
Page 19 of 21 
 

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