Phase I Study to Evaluate the Feasibility of Neoadjuvant Stereotactic Body Radiation Therapy for Resectable Adenocarcinoma of the Pancreatic Head and/or Body
Phase: NA
Conditions: Pancreatic Cancer
Sponsor: University of Cincinnati

 
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UCCI-GI-002- PHASE I STUDY TO EVALUATE THE FEASIBILITY OF 
NEOADJUVANT STEREOTACTIC BODY RADIATION THERAPY FOR 
RESECTABLE AND/OR BORDERLINE RESECTABLE ADENOCARCINOMA 
OF THE PANCREATIC HEAD AND/OR BODY 
 
Principal Investigator: Jordan Kharofa, MD 
  
 
 
Assistant Professor 
  
 
 
Department of Radiation Oncology 
  
 
 
University of Cincinnati 
 
Co-Investigators: 
 
  
 
 
Syed Ahmad, MD 
  
 
 
Kyuran Choe, MD 
  
 
 
Tahir Latif, MD 
  
 
 
Olugbenga Olowokure, MD 
  
 
 
Nathan Schmulewitz, MD 
  
 
 
Milton Smith, MD 
  
 
 
Jeffrey Sussman, MD 
  
 
 
 
 
 
Statistician:  
 
Changchun Xie, PhD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Table of Contents 
 
 
Section 
Page Number 
Abbreviation List 
3 
Protocol Synopsis 
4-6 
Schema 
7 
I.     Objectives 
9 
II.    Background 
9-11 
III.   Rationale 
11-14 
IV.  Methods 
14-17 
V.   Study Population 
17-18 
VI.  Risk/Benefit 
18-19 
VII. Compensation 
19 
VIII.Adverse Events: List and Requirements 
20 
IX.  Statistical Consideration 
20-23 
X.   Data Reporting and Regulatory Considerations 
23-24 
XI.  Correlative Studies 
24-25 
XII. Measurement of Effects 
25 
XIII.Response Criteria 
26 
References 
27-32 
Appendix I: Study Calendar 
33 
Appendix II: EORTC QLQ 30 
34-35 
Appendix III: EORTC QLQ PAN26 
36-37 
Appendix IV: Karnofsky Performance Status Scale 
38 
Appendix V: Definition of Menopausal Status 
39 
Appendix VI: Postop Course/Complication Datasheet 
40 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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ABBREVIATION LIST 
 
 
SBRT  
Stereotactic Body Radiotherapy 
RCT 
 
Randomized Controlled Trial 
IORT  
Intraoperative Radiation Therapy 
IGRT  
Image Guided Radiation Therapy 
CBCT  
Cone Beam CT 
EUS 
 
Endoscopic Ultrasound 
BED 
 
Biologic Equivalent Dose 
GTV 
 
Gross tumor volume 
ITV 
 
Gross Tumor Volume 
PTV 
 
Internal Target Volume 
QA 
 
Planning Target Volume 
PPI 
 
Quality Assurance 
RTOG  
Proton Pump Inhibitor 
CTCAE 
Common Toxicity Criteria for Adverse Events 
AE 
 
Adverse Event 
CR 
 
Complete Response 
PR 
 
Partial Response 
SD 
 
Stable Disease 
PD 
 
Progressive Disease 
IHC 
 
Immunohistochemistry 
NK Cells 
Natural Killer Cells 
HA 
 
hyaluronan 
D1R 
 
Dopamine Receptor 1

 
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PROTOCOL SYNOPSIS 
 
TITLE 
PHASE I STUDY TO EVALUATE THE 
FEASIBILITY OF NEOADJUVANT 
STEREOTACTIC BODY RADIATION THERAPY 
FOR RESECTABLE AND/OR BORDERLINE 
RESECTABLE PANCREATIC 
ADENOCARCINOMA 
STUDY PHASE/DESIGN 
Prospective, non-randomized phase I study of 20 
patients 
INDICATION 
Resectable and/or borderline resectable 
adenocarcinoma of the pancreas 
PRIMARY OBJECTIVE 
To evaluate rates of acute (within 3 months of 
treatment) gastrointestinal toxicity following 
fractionated Linac based SBRT for pancreatic 
tumors. Toxicities of note include any grade 3 or 
greater gastrointestinal toxicity. 
SECONDARY OBJECTIVES 
To evaluate rates of late (> 3 months after 
treatment) gastrointestinal toxicity following 
fractionated Linac based SBRT for pancreatic  
tumors. Toxicities of note include grade 2 or 
greater gastritis, enteritis, fistula, or ulcer and any 
other grade 3 or greater gastrointestinal toxicity. 
To evaluate local progression free survival, overall 
survival and metastasis-free survival rates after 
Linac based SBRT and subsequent resection in 
patients with resectable and/or borderline 
resectable pancreatic adenocarcinoma of the 
head and/or body. 
To develop and standardize Linac based SBRT 
delivery and dosimetric parameters. 
To estimate resection margin positivity (R0/R1) 
and pathologic complete response rate after 
neoadjuvant SBRT 
To evaluate pre- and post- SBRT patient reported 
quality of life (QOL)
TREATMENT 
After 3- 4 monthsof chemotherapy, patients will be 
enrolled to a single arm trial of stereotactic body 
radiotherapy (SBRT) in 5 fractions given over 15 
days.  They will then proceed to surgery after a 
break of 4-6 weeks.   

 
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INCLUSION CRITERIA 
• 
Age >18 years. 
• 
Karnofsky Performance Status >70% (see 
Appendix IV). 
• 
Histologically confirmed pancreatic 
adenocarcinoma of the head and/or body; 
at least the majority of the histopathologic 
specimen must be identified as 
adenocarcinoma.  
• 
Pancreatic tumors must be considered at 
least borderline resectable and/or 
borderline resectable at time of treatment 
planning. Definition of resectable and/or 
borderline resectable: no metastases, less 
than 180 degree involvement of hepatic 
artery, superior mesenteric artery or celiac 
artery 
• 
No active infection requiring hospitalization 
• 
If bilirubin > 2, patients must have a biliary 
stent placed prior to SBRT. 
• 
Patients must have acceptable organ and 
marrow function (see section “Inclusion 
Criteria, page 17-18). 
• 
Women who are not post-menopausal (as 
defined in Appendix V) should have a 
negative urine or serum pregnancy test. 
Women of childbearing potential must 
agree to use adequate contraception for 
the duration of study participation. 
• 
Ability to understand and the willingness to 
sign a written informed consent document. 
• 
Life expectancy > 3 months. 
• 
Patients are to have received neoadjuvant 
chemotherapy prior to enrollment.  
Approved regimens may consist of 3-4 
months of gemcitabine-based 
chemotherapy or FOLFIRINOX. Patients 
will have a 2-4 week break between last 
chemotherapy administration and start of 
SBRT

 
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EXCLUSION CRITERIA 
• 
Presence of metastatic disease. 
• 
Infections requiring systemic antibiotic 
treatment. 
• 
Unable to understand or unwilling to sign a 
written informed consent document. 
• 
 
PROCEDURES 
Endoscopically guided fiducial placement with 
optional biopsies obtained at the time of fiducial 
placement. 
STATISTICAL CONSIDERATIONS 
See statistics section. 

 
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SCHEMA 
 
Eligibility:  resectable or borderline resectable adenocarcinoma of the pancreas.  Definition of resectable: 
no metastases, less than 180 degree involvement of hepatic artery, superior mesenteric artery or celiac 
artery 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chemotherapy for  
3-4 months 
 
SBRT 6.6 Gy 
X 5 fractions 
 
Surgery 
2-4 week break 
4-6 week break 
Study Entry 

 
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I.  OBJECTIVES 
 
Primary Objective 
• 
To evaluate rates of acute (within 3 months of treatment) grade 3  or  greater 
gastrointestinal toxicity. 
 
Secondary Objectives 
• 
To evaluate rates of late (> 3 months after treatment) grade 2 gastritis, enteritis, fistula, 
and ulcer, or any other grade 3 or greater gastrointestinal toxicity 
• 
To determine rates of local progression free survival, overall survival, and metastasis- free 
survival in patients with resectable and/or borderline resectable pancreatic 
adenocarcinoma of the head and/or body undergoing neoadjuvant SBRT 
• 
To evaluate patient quality of life before and after Linac based SBRT. 
• 
To evaluate the margin positivity rate and pathologic complete response rate after Linac 
based SBRT. 
• 
To further develop standardization of Linac based SBRT delivery and dosimetric 
parameters. 
 
 
 
II.  BACKGROUND 
 
Natural History and Management of Pancreatic Cancer 
More than 40,000 individuals are diagnosed with pancreatic cancer annually in the United States. 
Despite aggressive combined modality treatment approaches, five-year survival of patients with 
pancreatic cancer is still less than 5% (1). Clearly, more innovative treatments are needed to 
improve survival in this group of patients. 
 
Surgical resection is considered to be the only potentially curative treatment option (2). However, 
the majority of pancreatic cancer patients do not have resectable and/or borderline resectable 
disease at presentation. More than 85% of patients have locally advanced or metastatic disease 
when initially diagnosed. 
 
Current Adjuvant Management of Resectable and/or borderline resectable Pancreatic 
Adenocarcinoma 
Among the minority of patients who are able to undergo surgical resection, low median survival 
rates and cure rates imply the presence of residual local and/or systemic microscopic disease 
that may be amenable to adjuvant therapy. The standard of care for adjuvant therapy is 
controversial. Adjuvant chemoradiation has been frequently studied due to high rates of positive 
margins and locoregional recurrences seen in surgical series. 
 
The benefit of 5-fluorouracil-based chemoradiation was first seen in a small, randomized trial 
performed by the Gastrointestinal Tumor Study Group (GITSG) (2).  This study, published in 
1985, randomized patients to observation versus postoperative therapy with concurrent 5-FU and 
split-course radiation (40Gy), followed by two years of adjuvant 5- FU. It showed a striking benefit 
in median survival and 5-year overall survival among patients undergoing chemoradiation despite 
the fact that there was no difference in loco-regional control among the two arms. The EORTC 
performed a similar study that enrolled patients with either pancreatic or periampullary cancers, 
who were randomized postoperatively to observation or chemoradiation (split-course radiotherapy 
with concurrent 5-FU). This protocol also demonstrated a trend towards improved survival among 
patients with pancreatic cancer who received adjuvant chemoradiation (3, 4). Additionally, two 

 
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large retrospective series, one from Johns Hopkins University (n=616) and one from the Mayo 
Clinic (n=472), have demonstrated median survival benefits consistent with the GITSG and 
EORTC studies (5, 6). 
 
The comparative benefit of chemotherapy and chemoradiation was challenged by the European 
Study Group for Pancreatic Cancer (ESPAC) study, which randomized 541 patients with 
pancreatic adenocarcinoma who had undergone surgical resection to the following four treatment 
arms using a two-by-two factorial design: a) observation; b) concomitant chemoradiotherapy (20 
Gy in 10 fractions over 2 weeks) with 500 mg/m2 5- FU IV bolus during the first three days of 
radiation therapy, repeated after a planned 2- week break without additional chemotherapy; c) 
chemotherapy alone (leucovorin 20 mg/m2 bolus followed by 5-FU 425 mg/m2 administered for 5 
consecutive days repeated every 28 days for 6 cycles); and 4) chemoradiotherapy (as in arm 2) 
followed by chemotherapy. For the same subset randomized through the original two by two 
design, chemotherapy alone demonstrated a trend towards improved survival alone (median 
survival 17.4 months) versus observation alone (15.9 months), but the difference was not 
statistically significant (p=0.19). The study authors concluded that there was no survival benefit 
for adjuvant chemoradiotherapy but that a potential benefit existed for adjuvant chemotherapy 
alone. Unfortunately, this trial had many flaws, including a questionable study design and lack of 
surgical/pathological/radiation quality control measures, rendering its results difficult to interpret. 
However, ESPAC does highlight the importance of adjuvant chemotherapy. 
 
While the above-mentioned adjuvant studies were being conducted, gemcitabine emerged as a 
more effective chemotherapy than 5-FU in the setting of advanced disease  (8). Because of this, 
gemcitabine was evaluated in the post-operative setting. The Radiation Therapy Oncology Group 
(RTOG) reported on a phase III study of 518 resected pancreatic cancer patients randomized to 
either 5-FU or gemcitabine. Dosing for the 5-FU group consisted of continuous infusion (250 
mg/m2/d for 3 weeks), followed by 5-FU continuous infusion (250 mg/m2/d) during radiation 
therapy (50.4 Gy in 1.8 Gy/fractions), followed by 2 cycles of 5-FU continuous infusion. Patients 
assigned to the gemcitabine arm received gemcitabine 1000 mg/m2 weekly X 3, followed by 5-FU 
continuous infusion during radiation therapy, followed by 3 cycles of gemcitabine alone (9). 
Although there was a higher incidence of grade 3-4 neutropenia among patients in the 
gemcitabine arm, the median survival was 20.3 months for the gemcitabine-treated patients 
versus 16.3 months for 5-FU treated patients (p=.03). In the final manuscript, RTOG reported a 
survival benefit on multivariable analysis of 20.6 versus 16.9 months (p=.03) in favor of the 
gemcitabine chemotherapy arm, restricted to patients with cancer of the pancreatic head. The 
European CONKO-1 study recently published a phase III study of 354 resected patients 
randomized to observation or 6 months of gemcitabine chemotherapy (10). The primary endpoint 
of this study was DFS; patients in the treatment arm had a significant improvement in DFS (13.4 
months v. 6.9 months, p<0.001). Further follow-up has shown a survival benefit to chemotherapy. 
 
From these studies, it is evident that a single standard adjuvant treatment approach for patients 
with resected disease has not yet been determined. However, given the above data, gemcitabine- 
or 5-FU based CRT (RTOG 9704) or gemcitabine/bolus 5-FU (CONKO- 1/ESPAC-3) can both be 
viewed as a reasonable standard of care in the adjuvant setting. 
 
Current Neoadjuvant Management of Resectable and/or borderline resectable Pancreatic 
Adenocarcinoma 
Among patients who have undergone surgery, pancreatic cancer exhibits a strong tendency to 
recur locally and to metastasize after a brief median time interval of approximately 13 months 
from surgical resection (11). Early relapse after curative surgery is likely explained by the 
presence of micrometastases or minimal residual primary disease not detectable at the time of 

 
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surgery, or by the spread of tumor cells into the portal vein, lymphatic vessels, and peritoneal 
cavity due to surgical manipulation. Therefore, preoperative treatment of resectable and/or 
borderline resectable or borderline resectable and/or borderline resectable pancreatic cancer has 
several potential benefits. 
 
First, patients who undergo surgery up front must wait at least 6-8 weeks after surgery for healing 
to occur before starting adjuvant CRT. Furthermore, 20-30% of patients are unable to receive 
planned adjuvant therapy due to surgical complications or inability to tolerate adjuvant therapy 
after surgery (12, 13). Thus, there is a potentially harmful delay in treatment of micrometastatic 
disease, which is thought to exist in a majority of resectable and/or borderline resectable patients. 
Neoadjuvant therapy avoids this delay, allowing for immediate treatment of micrometastatic 
disease. Second, approximately 30% of patients who undergo surgery have positive resection 
margins (11,14); if radial margins are examined, it appears that as many as 75% of resections are 
margin-positive (15). Any partial response to treatment reduces the tumor volume, potentially 
increasing the likelihood of an R0 resection while decreasing both the burden of microscopic 
residual disease and intraoperative tumor spillage. Third, the resected tumor can serve as its own 
biological marker of treatment response; that is, an in vivo assessment of tumor chemo/radio-
sensitivity can be performed. Fourth, the undisturbed tumor microenvironment may permit better 
delivery of chemotherapy to the tumor through the vasculature. An intact vascular supply will also 
allow for better oxygenation of tumor, which may enhance the effects of radiation by allowing for 
increased generation of oxygen free radicals. Fifth, without the prior trauma of surgery, the 
normal tissue surrounding the tumor may better tolerate CRT, decreasing rates of treatment- 
postponing toxicities and allowing for higher-dose radiotherapy. Sixth, patients who experience 
disease progression prior to surgical resection despite neoadjuvant therapy likely have tumors of 
an exceedingly aggressive biology that cannot be cured by extensive surgery and can therefore 
be spared the considerable risk of surgical morbidity and mortality. Finally, neoadjuvant CRT 
raises the possibility of downstaging unresectable and/or borderline resectable and borderline 
resectable and/or borderline resectable/unresectable and/or borderline resectable disease so that 
more patients ultimately are able to undergo potentially curative surgical resection. 
 
The main drawbacks of neoadjuvant treatment include: (a) possible delay of surgery due to 
complications of therapy, (b) the generally low response rate of advanced pancreatic cancer to 
multimodality treatments, and (c) the potentially higher surgical complication rate due to prior 
irradiation of tissue at the resection site. Encouragingly, no increase in surgical complications 
after neoadjuvant therapy has been reported to date (16-18). 
 
To date, no large randomized controlled trials have studied neoadjuvant therapy for resectable 
and/or borderline resectable pancreatic cancer, and the sample size of existing prospective series 
has been small (see table II). Despite the theoretical advantages of neoadjuvant therapy, results 
obtained to date have shown only modest improvements compared to surgery alone. Median 
survival and 2-year OS for patients receiving neoadjuvant therapy range from 8-23 months and 
from 27-40%, respectively (19-23), compared to 11-17 months and 15-31% for surgery alone 
(24,25). Meanwhile, adjuvant chemoradiation (CRT) has produced a median survival of 27-44 
months and 2-year OS of 53-58% (26-28). Thus, while neither neoadjuvant nor adjuvant CRT 
have achieved major degrees of improvement in OS, both have been demonstrated to be slightly 
more effective than surgery alone for pancreatic adenocarcinoma. The current prevailing 
management strategy, therefore, is to combine neoadjuvant chemotherapy and/or radiation, 
surgical resection, and adjuvant chemotherapy and/or radiation to  achieve  the  highest possible 
rate of long-term survival, though no RCTs have yet been done to conclusively prove the efficacy 
of this regimen. 
 

 
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III.  RATIONALE 
 
Rationale for Radiotherapy in Treatment of Pancreatic and Periampullary 
Adenocarcinomas 
Radiation therapy is a widely accepted treatment for pancreatic cancer. The Gastrointestinal 
Tumor Study Group (GITSG) carried out a series of landmark studies demonstrating the 
effectiveness of radiation therapy as both adjuvant and definitive treatment in pancreatic cancer 
(6,7). Modern radiation treatments have increasingly used conformal fields and dose escalation to 
enhance tumor control (8, 9). Efforts to increase radiation dose to the pancreatic tumor without 
risking normal tissue injury have generally required relatively invasive techniques such as 
interstitial implantation of radioactive metals or intraoperative radiotherapy (IORT) (10, 29). 
Historically, the local control rates  for conventionally fractionated radiotherapy have  ranged from 
25-50%. Local progression of pancreatic cancers can result in considerable morbidity, including 
gastric outlet obstruction, biliary obstruction, and pain (30).  
 
Rationale for Fractionated Stereotactic Radiotherapy 
The mortality rate for pancreatic cancer approaches 100%. Current therapies provide only partial 
palliation of symptoms and slight prolongation of survival. More effective therapies are clearly 
needed. Several clinical trials have shown that Linac based SBRT has the potential to 
significantly improve progression-free survival of patients with pancreatic tumors, which could 
translate into both more effective palliation and longer patient survival. 
 
Linac based SBRT is delivered using linear accelerators and image-guided radiation therapy 
(IGRT). These machines combine a conventional high-energy linear accelerator with a kV imager 
capable of volumetric, cone beam CT (CBCT). Because of these innovations, it is possible to 
deliver highly accurate, stereotactic radiation treatments. 
 
Koong et al. previously used the CyberknifeTM stereotactic radiosurgery system to demonstrate 
that a single dose of 25 Gy Linac based stereotactic body radiotherapy (SBRT) was feasible for 
patients with locally advanced pancreatic cancer (36). Furthermore, this dose of radiation resulted 
in near 100% progression free survival and effectively palliated symptoms related to the local 
growth of pancreatic tumors. Based on this study, the same group also completed a phase II 
study assessing the efficacy of combining a standard five- week course of chemoradiotherapy 
followed by a stereotactic radiosurgery boost to the primary tumor in patients with locally 
advanced pancreatic cancer. In this cohort of 19 patients, 100% of tumors were without local 
progression at 1 year median follow-up. However, all patients eventually developed metastases.. 
 
More recently, another phase II study treated locally advanced pancreatic cancer patients with 
gemcitabine followed by 25 Gy of Linac based SBRT delivered with Cyberknife and maintenance 
gemcitabine chemotherapy. In this study, the excellent progression free survival was confirmed 
from previous studies (81%).  The median overall survival was 11.4 months, median time to 
progression was 9.7 months and the 1 year survival was 50% (37). There were no significant 
acute GI toxicities however, of the 15 patients alive >6 months after Linac based SBRT, 7 (47%) 
experienced Grade 2 or greater GI toxicity, with 2 (13%) of the 15 experiencing Grade 3 or 
greater GI toxicity. 
 
A multi-institutional study (Johns Hopkins, Stanford, Memorial Sloan Kettering) of fractionated 
SBRT (6.6Gy x 5) in 70 patients with locally advanced or borderline resectable and/or borderline 
resectable pancreatic adenocarcinoma has thus far shown very promising results.  Median overall 
survival of the locally advanced patients was 13.9 mo (comparable to national standard) with 83% 
local control at 1 year.  Furthermore, patients reported improved global and pancreas specific 

 
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quality of life post-SBRT (Herman, ASTRO oral presentation, Sept 2013).  Rates of acute and late 
GI toxicity have been < 15%, Grade 2 or less with no grade 3 or higher toxicity seen.  Seventeen 
of these patients have gone to resection thus far, with no complications, and 50% pathologic 
complete response rate, 90% negative margin resection rate, and 80% node negative rates 
(Herman, personal communication).  Given these very encouraging pathologic results, while 
SBRT can be delivered faster and with fewer side effects than traditional fractionated 
radiotherapy, we are interested in fractionated SBRT for resectable and/or borderline resectable 
patients.   
 
To date, Stanford has treated more than 150 patients with Linac based SBRT for locally 
advanced or borderline resectable and/or borderline resectable pancreatic cancer, and this 
treatment has resulted in local control rates of >90% with acceptable acute GI toxicity. We predict 
that this treatment will not adversely impact patients’ quality of life. Although QOL measures have 
not been thoroughly studied among pancreatic cancer patients treated with Linac based SBRT, 
the majority of patients treated with Linac based SBRT appear to derive a clinical benefit as 
assessed by decreased pain, decreased fatigue, and increased weight. A single fraction of Linac 
based SBRT (25 Gy x 1) has resulted in excellent tumor control. However, close to 50% of these 
patients developed late duodenal toxicity within one year, primarily because of the proximity of 
the duodenum to the pancreas. 
 
Although we believe this schedule (5 Gy x 5 or 6.6 Gy x 5) will result in good tumor control and 
acceptable toxicity, the potential clinical efficacy of this short-course, hypofractionated regimen is 
unknown in resectable and/or borderline resectable pancreas cancer. The choice of this regimen 
as a potentially effective approach for resectable and/or borderline resectable pancreatic cancer 
treatment is based on the following observations: First, a similar schedule (5 Gy x 5) has been 
widely and efficaciously used in the neoadjuvant setting for rectal cancer, although a much larger 
field is used. Additionally, a series of patients with resectable and/or borderline resectable 
pancreatic lesions treated at the M.D. Anderson Cancer Center strongly suggest that a 5-FU 
based chemoradiation regimen consisting of 30 Gy in 10 fractions over 2 weeks reduces 
treatment time and toxicity compared with a regimen consisting of 50.4 Gy in 28 fractions over 5 
to 6 weeks without compromising overall survival or local control. Hong et al. from Massachusetts 
General Hospital have reported on a neoadjuvant regimen delivering 5 Gy x 5 to the pancreatic 
tumor plus adjacent lymph nodes using proton beam radiation (41). They show this regimen to be 
safe, with no instances of dose limiting toxicity observed and only 4 of 15 patients developing 
grade 3 toxicity (no patients experienced grade 4 toxicity). Finally, in the multi-institutional study 
of patients with locally advanced or borderline tumors treated with 6.6Gy x 5 at Johns Hopkins, 
Stanford or Memorial Sloan Kettering, there have been no significant peri-operative complications 
seen with very encouraging pathologic results previously mentioned above (Herman, personal 
communication).   
 
The phase I feasibility study outlined in this protocol proposes a 6.6 Gy x 5 fractionation schedule 
treating the region of tumor plus a 3 mm margin. These volumes will be substantially smaller than 
the regimens outlined above for rectal and pancreatic cancer, likely leading to a lesser degree of 
toxicity. Using the linear-quadratic formulation, the biologically equivalent dose (BED) of the two 
proposed fractionation schedules are given in comparison to other commonly used schemes 
(table 1). The BED of the proposed 6.6 Gy x 5 schedule (BED early/late 54.8/105.6) closely 
approximates that of standard chemoradiation (BED early/late 60/83.3), but without concurrent 
chemotherapy and treating (0.3  cm vs.  ~2  cm).  Furthermore,  the  proposed  6.6  Gy  x  5 
fractionation schedule has a much lower late BED (105.6 vs. 233.3) with a similar early BED 
(54.8 vs. 87.5) as the previous 25 Gy x 1 regimen that has resulted in higher toxicity. 
 

 
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Table 1: 
Nodes Tx Concurrent 
Chemo
BED early BED late 
a/b=10 
a/b=-3 
50.4 
Yes 
5-FU 
60 
83.3 
30 Gy/10 Yes 
Gemcitabine 39 
60 
25 Gy/5 No 
No 
37.5 
66.7 
33 Gy/5 No 
No 
54.8 
105.6 
25 Gy/1 No 
No 
87.5 
233.3 
 
In this study, we will refine our current understanding of radiation tolerance of the pancreas and 
adjacent organs, thereby making it possible to treat future patients more safely and aggressively. 
 
The major benefit of Linac based SBRT/chemotherapy for resectable and/or borderline resectable 
pancreatic tumors is improved local control from improved sterilization of primary tumor and 
lymph nodes, and well as faster delivery with lower side effects. In addition, radiosurgical ablation 
of the tumor at the primary site early after diagnosis can theoretically prevent distant seeding from 
the pancreatic tumor itself. Ultimately, these improvements in the treatment of pancreatic cancer 
may translate into an improved quality of life and overall survival. 
 
Quality of life will be assessed using the European Organization for Research and Treatment in 
Cancer quality of life core cancer questionnaire with the pancreatic cancer module (EORTC QLQ-
C30/PAN26). The EORTC QLQ-C30 is a multidimensional, 30- item questionnaire, which 
assesses five functional scales (physical, role, cognitive, emotional, and social), three symptom 
scales (fatigue, pain, and nausea/vomiting), a global health/QOL scale, as well as 6 single items 
(42). The EORTC QLQ-PAN26 supplements the core questionnaire with 26 items specific for 
patients with pancreatic cancer (43,44). These instruments have been validated in patients 
receiving treatment for metastatic and resected pancreatic cancer and are sensitive to identify 
treatment related changes in quality of life. The quality of life of patients in this study will be 
compared to historical cohorts of patients treated with conventional chemoradiation at University 
of Cincinnati and other institutions. 
 
IV.  METHODS 
 
REGISTRATION PROCEDURES 
 
General Guidelines 
Subjects will be identified per the recommendation of Surgeons, Medical Oncologists, Radiation 
Oncologists or GI Combined Modality Tumor Board or equivalent combined modality assessment.   
Subjects will be recruited through self-referral and the advice of their attending physician. Patients 
will be enrolled prior to start of SBRT.  Patients will  have chemotherapy (3-4 months) for 
pancreas cancer prior to study enrollment.  
 
Registration Process 
A member of the research team (most likely the research coordinator) will enroll the patient into 
the trial. Consent will be obtained after a clear and thorough discussion between the patient and 
the principal investigator or any of the co-investigators in clinic.  Any patients that are deemed by 
the principal investigator or co-investigators to be mentally or physically incapable of consent will 
not be included in the study. 

 
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SBRT ADMINISTRATION AND RADIATION TREATMENT PLANNING 
 
Pre-Linac based SBRT Tests, Procedures, and Planning 
 
The following will be completed prior to Linac based SBRT: 
• 
Signed informed consent document. 
• 
Medical history and clinical examination. 
• 
CBC with differential, Chemistry Panel, CA19-9. 
• 
Gold fiducial seed placement percutaneously, intraoperatively, or under endoscopic 
ultrasound guidance, technique will be determined clinically.  Fiducial placement may be 
performed prior to enrollment. 
• 
Pathologic confirmation of malignancy.  (Core biopsies during gold fiducial placement as 
needed or optional).  Patients are encouraged but not required to have tissue banked in 
UCCI Tumor Bank per Tumor Bank protocol. 
• 
Pancreas protocol CT required; if patient allergic to contrast and allergy can not be 
premedicated with steroids prior to IV contrast, pancreas protocol MRI will be obtained 
• 
Baseline collection of EORTC QLQ C-30/ PAN26 QOL. 
 
Fiducials 
Treatment on this protocol requires placement of 1-5 gold (99.9% pure, 1-5 mm length, or 
visicoils) fiducials for targeting purposes. The fiducials will be used as surrogates for targeting the 
daily tumor position during treatment. The fiducials will be placed directly into the tumor and/or 
periphery under endoscopic ultrasound or CT guidance. When possible, clips or fiducials will also 
be placed in the proximal duodenum directly adjacent to the pancreatic tumor. Fiducials may be 
implanted prior to enrollment as this is an acceptable standard of care procedure for any patient 
receiving radiotherapy for pancreatic cancer.  
 
If fiducials are not placed intraoperatively and/or prior to enrollment, placement will be done and 
is expected to be done on an outpatient basis. In rare occurrences when fiducials/clips cannot be 
placed, patients may be treated at the discretion of the PI. 
 
 
Simulation 
Simulation should be done following placement of fiducials; however, this may vary and is at the 
discretion of the principal investigator.  Typically, patients will be positioned supine in an Alpha 
Cradle or equivalent immobilization device that will be custom-made for each patient.  Standard 
free-breathing CT and respiratory-correlated 4-D pancreatic protocol CT will be obtained on each 
patient. The 4D-CT scan will be used for characterizing target motion during quiet respiration. For 
more accurate tumor delineation, an arterial phase pancreatic protocol CT may be obtained 
(typically during expiration breath hold, 1.25 mm slices). Fiducial to fiducial fusions between  
these  scans  should  be  utilized  whenever  possible.  The simulation scan should include T4/T5 
to L5/S1 (upper abdomen).  IV and oral contrast must be used for simulation, unless the patient 
has an allergy that cannot be adequately premedicated. In these situations, the plan should be 
fused with an IV contrast CT scan or MRI (ideally in a similar treatment position).  Motion 
management can be addressed using respiratory gating, breath-hold, respiratory tracking, or 
abdominal compression. Specialized compression belts may be utilized for some patients. Each 
belt has an adjustable pressure cuff which can be used to reduce breathing motion.  Fluoroscopy 
is used to assess motion of implanted gold markers before and after compression.  The goal is to 
reduce motion from typically 11-22 mm peak to less than 5 mm. If the fiducial motion cannot be 
decreased to 5 mm or less, then respiratory gating will be utilized for treatment delivery. Prior to 

 
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simulation, standard guidelines will be followed.  As long as the specified dosimetric parameters 
for SBRT are reached, patients may be treated on any IGRT-enabled machine. 
All patients must start Linac based SBRT within 4 weeks of the simulation scan. 
 
Treatment Planning 
An SBRT treatment plan will be developed based on tumor geometry and location. Institutional 
standards for radiation quality assurance and radiation delivery will be utilized.  The tumor volume 
(GTV), as identified on the treatment planning CT, will be contoured by an attending physician 
from UC Radiation Oncology. The final GTV will be defined by the attending radiation oncologist 
after reviewing the diagnostic CT, respiratory-correlated 4D-CT scan, pancreas protocol CT scan. 
These scans will be used to define the ITV (internal target volume). The final PTV(planning 
treatment volume) expansion will consist of an additional 2-3mm of margin expansion of the 
primary tumor to generate the PTV primary, except if the margin results in expansion into the 
duodenum or stomach. In these cases, margin expansion is allowed to be non-uniform. The dose 
will be prescribed to the isodose line that completely surrounds the PTV primary. It is 
recommended that 6-12 co-planar fields be used in the radiation treatment plan. A low dose 
clinical target volume will also be incorporated in the treatment volume called CTV vasculature. 
This customized CTV volume covers the immediately abutting vasculature (SMA, celiac, SMV), 
the pathway of perineural spread to the root of the mesentery, and extrapancreatic tissue 
immediately adjacent to the primary tumor at the discretion of the radiation oncologist. A 3 mm 
PTV margin will be added to the CTV vasculature to generate the PTV vasculature. The dose to 
this structure will receive 25 Gy over the 5 fraction SBRT course.  
 
Contours of the fiducials used for target localization will be generated on the applicable image 
sets, to be used for patient setup on treatment.  Radiation dose to the adjacent normal tissue will 
be minimized. Based on an analysis of duodenal toxicity representing pooled data from 3 
previous prospective studies, the following dose constraints must be met: V15<9cc, V20<3cc. 
The duodenum (duo@PTV) as defined for these dosing parameters includes the entire 
duodenum on the same axial plane as the PTV and duodenum 1 cm above and 1 cm below the 
PTV. V15 and V20 are defined as the percent volume receiving 15 Gy and 20 Gy, respectively. 
The remainder of the normal tissues will be limited as follows: 
 
• 
Liver (excluding tumor): 50% should be limited to <12 Gy  
• 
Kidney: Combined volume for both should have 75% <12 Gy  
• 
Stomach and duodenum: V15<9cc and V20<3cc.  50% should be limited to <12 Gy (no 
more than 1 cc of proximal stomach can receive >33 Gy)  
• 
Spinal Cord: no more than 1cc can receive >8 Gy 
 
No more than 1cc of the PTV primary can receive >130% of the prescription dose (4290cGy for 
6.6Gy x 5). 
Greater than 90% of the PTV primary should receive 100% of the prescription dose (3300cGy for 
6.6Gy x 5) 
Greater than 90% of the PTV Vasculature should receive 100% of the prescription dose (2500 for 
5 Gy x 5) 
 
If above constraints cannot be achieved, then 100% of the GTV must receive at least 25 Gy (an 
allowed minor deviation, which will be documented).  If this constraint cannot be met, the patient 
should be removed from the protocol. 
 
Linac based SBRT Treatment Delivery 
Patients will receive 5 fractions of 6.6 Gy delivered twice weekly, with each fraction separated by 

 
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> 48 hours.  Radiotherapy will be delivered Monday- Friday at Precision Radiotherapy or Barrett 
Cancer Center.  Initial patient positioning will be based on volumetric kV (cone-beam CT) imaging 
with shifts to bony anatomy as appropriate.  Orthogonal kV/MV or kV/kV projection imaging will 
be used to verify the location of the fiducials prior to delivery of first treatment beam.  A secondary 
shift based on the location of fiducials may be utilized, as indicated by the position of the fiducials. 
For free-breathing treatments, kV fluoroscopic images should be obtained to confirm the 
anticipated position of these fiducials during the entire respiratory cycle.  Active monitoring of 
treatment delivery accuracy will be accomplished using kV and/or MV projection imaging, either 
immediately before or during all (or a subset of) treatment fields. 
Patient-specific dosimetric quality assurance (QA) will be performed as per standard practice in 
the Department of Radiation Oncology at University of Cincinnati. 
 
Post-Linac based SBRT Follow-Up 
Following Linac based SBRT, all patients will be monitored clinically and with serial imaging (CT 
scans and/or PET/CT if possible and as deemed necessary by the treating physician).  A detailed 
medical history with physical examination and quality of life assessment will be performed at 4-6 
weeks, 3 months, 6 months, 9 months and 1 year after radiation treatment.  In years 2-5, the 
follow up interval will be every 3-6 months, as determined by the principal investigator. Follow up 
intervals may also be more frequent as indicated clinically. A complete blood count (CBC) with 
differential, comprehensive chemistry panel, tumor marker studies, and quality of life assessment 
will be performed at each follow-up interval. 
 
GENERAL CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES 
 
Anti-diarrheals and Anti-emetics 
For symptoms of diarrhea and/or abdominal cramping, patients will be instructed to take anti-
diarrheals. Additional antidiarrheal measures may be used at the discretion of the treating 
physician. Patients should be instructed to increase fluid intake to help maintain fluid and 
electrolyte balance during episodes of diarrhea.  For symptoms of nausea and vomiting, anti-
emetics will be given one hour prior to Linac based SBRT and for up to 5 days following Linac 
based SBRT on an as- needed basis. Additionally, patients will be instructed to increase fluid 
intake.  All patients will be prescribed proton pump inhibitors (PPIs), which should begin by the 
start of Linac based SBRT and continue for a minimum of 6 months following Linac based SBRT. 
 
Other Concomitant Medications 
Therapies considered necessary for the patient's well being may be given at the discretion of the 
investigator. Other concomitant medications should be avoided except for analgesics, chronic 
treatments for concomitant medical conditions, or agents required for life-threatening medical 
problems. Specifically, if the patient is being treated with chemotherapy, it is recommended that 
chemotherapy be discontinued at least one week prior to initiation of Linac based SBRT and that 
resumption of chemotherapy be delayed for at least one week following the conclusion of Linac 
based SBRT. In general, prescription of these medications will be presided over by the patient’s 
attending medical oncologist. 
 
Supportive Care Guidelines 
All commonly accepted supportive care guidelines will be used. 
 
Use of Radioisotopes/Rad Machines 
Stereotactic radiotherapy will be performed using Linac based radiation machines. The radiation 
treatment plan will be designed to use multiple beams of radiation to concentrate large doses of 
radiation within a tumor. The Linac machines are equipped with cone beam CT imaging that can 

 
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be used to deliver image-guided radiation therapy (IGRT). IGRT allows delivery of highly 
accurate, stereotactic radiation treatment. The use of cone beam CT images during IGRT is 
considered standard of care treatment.  Uncertainties in tumor location are minimized because 
these machines have on- board, volumetric imaging for accuracy in initial patient setup; kV and 
MV projection imaging during treatment is used to monitor delivery accuracy and/or make 
corrections to the patients’ position.  
 
V.  STUDY POPULATION 
 
PATIENT SELECTION 
Inclusion Criteria 
• 
Age >18 years. 
• 
Karnofsky Performance Status >70% (see Appendix IV). 
• 
Histologically confirmed adenocarcinoma of the pancreatic head and/or body; at least the 
majority   of   the   histopathologic   specimen   must   be   identified   as adenocarcinoma 
as opposed to another histologic subtype. 
 
o *If histological confirmation of adenocarcinoma cannot be obtained by biopsy, the 
following procedures may be employed: 
 
Attempt a repeat biopsy to obtain a diagnosis. 
 
Present the case at UC tumor board and if the candidate has one of the 
following: a rising CA 19-9 or radiographic evidence of pancreas tumor on 
MRI, CT, and/or PET scan then the patient can be considered for treatment 
on protocol. 
 
However, if these objectives cannot be met, the patient will not be a 
candidate. 
 
 
• 
Pancreatic tumor must be considered at least borderline resectable by UC multi-
disciplinary tumor board at the time of treatment planning.  
• 
Patients who have not received RT to the abdomen. 
• 
Patients must have acceptable organ and marrow function as defined below (within 2 
weeks prior to radiotherapy): 
• 
Leukocytes >3,000/µL 
• 
Absolute neutrophil count >1,500µL 
• 
Platelets >100,000/µL 
• 
Total Bilirubin ≤2X normal institutional limits 
• 
AST(SGOT)/ALT(SGPT) <2.5X institutional upper limit of normal 
• 
Pre-menopausal women must have a negative serum pregnancy test 
• 
If bilirubin > 2, all patients must have a biliary stent placed prior to radiotherapy.  After 
stent placement, bilirubin must be <1.5x normal prior to study entry. 
• 
Creatinine ≤ institutional upper limit of normal 
OR 
• 
Creatinine clearance >60 mL/min/1.73 m2  for patients with creatinine levels above 
institutional normal 
• 
Ability to understand and  the  willingness  to  sign  a  written  informed  consent 
document. 
• 
Patients are to have received neoadjuvant chemotherapy prior to enrollment (3-4 months). 
Approved regimens may consist of 3-4 months of gemcitabine-based chemotherapy or 
FOLFIRINOX. Patients will have a 2-4 week break between last chemotherapy 

 
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administration and start of SBRT.  
• 
Patient must be able to have fiducials placed. If not, the tumor must be posterior and 
adjacent to the aorta and treatment will only be permitted at the discretion of the Principal 
Investigator. 
 
 
Exclusion Criteria 
• 
Children (< 18 years) are excluded because pancreatic tumors rarely occur in this age 
group. Furthermore, treatment requires a great deal of patient cooperation including the 
ability to lie still for several hours in an isolated room. 
• 
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection (or 
infections requiring systemic antibiotic treatment), symptomatic congestive heart failure, 
unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that 
would limit compliance with study requirements. 
• 
Pregnant and breastfeeding women are excluded as are women of child-bearing potential 
who are unwilling or unable to use an acceptable method of birth control (hormonal or 
barrier method of birth control; abstinence) to avoid pregnancy for the duration of the 
study treatment. Should a woman become pregnant or suspect she is pregnant while 
undergoing radiotherapy in this study, she should inform her treating physician 
immediately. 
• 
Women who are not post-menopausal (as defined in Appendix V) and have a positive 
urine or serum pregnancy test or refuse to take a pregnancy test. 
 
VI.  RISK / BENEFIT 
 
Risk Information 
It is difficult at this time to predict with confidence the percentage rate of complications from the 
proposed Linac based SBRT treatment. However, it is reasonable to extrapolate from the current 
experience with radiotherapy in and around the pancreas. Based upon prior phase I and phase II 
studies, we anticipate that the toxicities associated with this treatment will be acceptable.   
 
Toxicities commonly associated with such treatment include nausea, vomiting, fatigue, anorexia 
and weight loss. Severe side effects such as gastrointestinal (GI) obstruction, perforation, or 
hemorrhage are uncommon complications, occurring in <5% of patients undergoing standard 
radiation therapy for pancreatic cancer. Although we expect a comparable rate of complications 
with fractionated Linac based SBRT, it is important to note that vomiting, GI obstruction, GI 
hemorrhage, anorexia and weight loss are also commonly associated with pancreatic cancer 
progression. Clinical and radiographic assessments will be performed in an effort to identify these 
effects, ascertain their etiology and provide the most appropriate palliative measures. Hepatic and 
renal toxicity is not anticipated given the expectation of limited incidental irradiation of these 
organs. Complications, if any, will be graded according to the CTCAE, National Cancer Institute, 
version 4.0. We will also utilize the RTOG scale for grading acute and chronic radiotherapy 
toxicities. 
 
Duration of Study 
It is anticipated that this study will last approximately 36 months (24 months of accrual and 12 
months while cohort matures). 
 
Duration of Follow Up 
We estimate that most patients will remain a subject in this study for approximately one year.  
Patients will remain enrolled on this protocol for a maximum of 5 years or until patient withdrawal. 

 
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One year after Linac based SBRT, patients should undergo standard follow-up every 3-6 months, 
as determined by the treating physician. Patients that have completed the 5 year follow-up will 
continue being followed for survival information until death. The administration of subsequent 
chemotherapy and/or other antineoplastic treatment following Linac based SBRT will be at the 
discretion of each patient’s attending medical oncologist. 
 
Criteria for Removal from Study 
Patients will be removed from the study for any of the following reasons: death or patient 
withdrawal. The protocol director may also withdraw a patient from the study for one or more of 
the following reasons:  failure of the patient to follow the instructions of the protocol study staff, 
the protocol director decides that continuing participation could be harmful to the patient, 
pregnancy (if applicable), the patient needs treatment not allowed in the study, the study is 
cancelled, other administrative reasons, or unanticipated circumstances. Patients that have been 
removed from or discontinue the study will be followed for survival information until death. 
 
Alternatives 
Alternative therapies include chemotherapy alone, standard chemotherapy/radiation, upfront 
resection of pancreas tumor, palliative symptomatic relief, or no further treatment. Additionally, 
patients may choose to receive treatment to improve quality of life but that may have no effect on 
the growth of their cancer. The risks of chemotherapy and standard chemotherapy/radiation 
include nausea, vomiting, diarrhea, fatigue, bone marrow suppression, and sepsis.  The potential 
benefits of chemotherapy or standard chemotherapy/radiation are prolonged survival.  The risk of 
pursuing no further treatment is tumor progression or spread. 
 
VII.  COMPENSATION 
 
Subjects will not be paid to participate in the study. 
 
 
VIII.  ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS 
 
Adverse Events and Potential Risks List 
Based upon prior phase I and phase II studies evaluating the toxicities associated with Linac 
based SBRT for pancreatic cancer, we estimate that ≤20% of patients will experience grade 2 or 
higher late GI toxicity within one year. Late GI toxicities are those events occurring more than 3 
months after Linac based SBRT. Acute GI toxicities are those events occurring within 3 months 
following Linac based SBRT. The major toxicity in this group of patients is the development of 
duodenal/gastric ulcers.  Most of these are successfully managed medically.  However, Stanford 
has observed 2 cases of duodenal perforation associated with Linac based SBRT in patients who 
did not undergo surgical resection of their tumors. We anticipate that because of refinements in 
radiation treatment planning techniques and because the dose will be divided over five treatments 
(as opposed to one), the biological equivalent and actual dose to the duodenum will be less than 
prior studies. Furthermore, the Stanford observed perforations occurred in duodenal locations 
that are routinely removed with pancreaticoduodenectomy, and all of our patients are anticipated 
to go to surgery.  We anticipate that the risk of ulcer formation should be low (< 5%) in this study. 
Hepatic and renal toxicity is not anticipated given the expectation of limited incidental irradiation 
of these organs.  
 
Reporting of Serious of Unexpected Adverse Events 
All fatal events, both anticipated and unanticipated, must be reported to the UC IRB within a time 
period as specified by current institutional guidelines after the PI learns of the  event, whether or 

 
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not the PI believes the event to be related to the study.  All  other  events,  which  are  both  
serious  and  unanticipated,  must  be reported to the UC IRB within a time period as specified by 
current institutional guidelines after the PI learns of the event. Events which are serious, but 
anticipated, should be reported as part of the continuing review application. If any of these 
Serious Adverse Events requires a change to the protocol or consent form, the PI must make 
those changes promptly and submit the revised documents to the UC IRB.  Important Adverse 
Events that are unanticipated must be reported to the UC IRB within a time period as specified by 
current institutional guidelines. If the Important Adverse Event requires changes to the protocol or 
consent form, the PI must make those changes promptly and submit the revised documents to 
the UC IRB.  All other unanticipated Adverse Events or changes to the protocol and consent form 
must be reported to the UC IRB, within a time period as specified by current institutional 
guidelines.  
 
 
IX.  STATISTICAL CONSIDERATIONS 
 
Study Overview 
This pilot study is designed to assess the feasibility of giving neoadjuvant SBRT in resectable 
and/or borderline resectable pancreas cancer patients.  The feasibility demonstration will 
establish the infrastructure for future randomized phase II clinical trials in a single or multi-center 
setting. Twenty patients with resectable and/or borderline resectable pancreas cancer, confirmed 
by multi-disciplinary radiologic review, will be enrolled and treated. The decision regarding 
whether this study demonstrates sufficient feasibility to support a phase II study testing novel 
regimens in this disease population will be based on three key considerations: 
• 
The study can meet the accrual goal. 
• 
The proposed preoperative SBRT will result in no more toxicity than has been established 
previously in the borderline resectable and locally advanced setting by evaluating the 
prevalence of grade 3+ toxicities and treatment delay rate (> 4 weeks). 
• 
The completion rate of preoperative and operative therapy meets the goals. 
 
Sample Size 
A maximum of 20 patients will be enrolled if the trial completes accrual. 
 
Accrual time 
The anticipated monthly accrual rate is approximately 1-2 patients per month.  The trial is 
expected to accrue in approximately 24 months. 
 
Statistical Design for Primary Endpoints 
 
Primary Endpoints 
• 
The primary endpoint is the rate of acute (within 3 months of treatment) G3+ 
gastrointestinal toxicities as assessed by CTCAE v4.0. 
 
Study Design and Decision Rules 
The purpose of this study is to demonstrate the feasibility of conducting a study assessing the 
proposed regimen. The sample size of twenty patients with confirmed resectable or borderline 
resectable pancreas cancer is selected based on financial and logistic considerations. However, 
we still propose decision rules based on testable hypotheses whenever possible. If, at the 
conclusion of the trial, none of the following stopping rules has been crossed, we will conclude 
that the proposed regimen and trial design warrants further phase II study for assessing  SBRT 
followed  by surgery in this disease population.  

 
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Accrual stopping rules 
If, 4 months following the date IRB approval is obtained, no patients have been accrued, we will 
conclude the study does not demonstrate sufficient feasibility.  Thereafter, the accrual rate will be 
monitored bi-monthly. If at any evaluation time point, the accrual rate is less than 0.5 per month, 
we will conclude the study does not demonstrate sufficient feasibility.  
 
Toxicity Stopping Rules 
The toxicity feasibility stopping rules are specified as the following: 
 
• 
The toxicity rate is defined as the proportion of treated patients with resectable and/or 
borderline resectable pancreas cancer who experience at least one grade 3+ adverse 
event, and is considered at least possibly related  to  the  preoperative  treatment (i.e. an  
adverse  event with attribute specified as “possibly,” “probably,” or “definitely” related to 
SBRT). The toxicity rate will be evaluated when the first 10, the first 15 and then 20 
patients are enrolled and the toxicity data are available.  
o When toxicity data are available on the first 10 evaluable patients, if the toxicity 
rate is greater than 0.54 (> 5 patients experienced defined AEs), we will conclude 
the study does not demonstrate sufficient feasibility. Otherwise, continue accrual. 
o When toxicity data are available on the first 15 evaluable patients, if the toxicity 
rate is greater than 0.46 (> 6 patients experience defined AEs), we will conclude 
the study does not demonstrate sufficient feasibility. Otherwise, continue accrual. 
o When toxicity data are available on all 20 evaluable patients, if the toxicity rate is 
greater than 0.42 (>8 patients experience defined AEs), we will conclude the study 
does not demonstrate sufficient feasibility. 
 
This decision rule based on a sample size of  20  patients  will have more 
than 80% chance to conclude the study does not demonstrate sufficient 
feasibility if the toxicity rate is ≥ 50% and only have less than 17% chance 
to conclude the study does not demonstrate sufficient feasibility if the 
toxicity rate is ≤ 30%. 
o If 4 or more patients in the first 10, or after 10 patients, 40% or more treated 
patients experience treatment delay (> 4 weeks), we will conclude the study does 
not demonstrate sufficient feasibility. 
 
Completion of Therapy Stopping Rules 
The completion of therapy stopping rules are specified as the following: 
 
• 
If at least 6 patients among 20 evaluable patients complete all preoperative and  operative  
therapy  including  R0 or R1  resection,  we  will  conclude  the study warrants further 
phase II study, provided that none of the other feasibility stopping rules are crossed at any 
time. 
 
• 
If 5 or less than 5 patients among 20 evaluable patients complete all preoperative and 
operative therapy we will conclude that the study does not demonstrate sufficient 
feasibility. 
 
o This decision rule based on a sample size of 20 patients will have more than 80% 
chance to conclude the study does not demonstrate sufficient feasibility if the 
R0/R1 resection rate is ≤ 20% and only have less than 13% chance to conclude 
the study does not demonstrate sufficient feasibility if the R0/R1 resection rate is ≥ 
40%. 

 
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Analysis Plan 
All acute AE (within 3 months after treatment) and the maximum grade for each type of adverse 
events (including all adverse events and those that are possibly, probably or definitely related to 
study treatments) will be recorded for each patient. The frequency tables will be reviewed to 
determine the patterns. Point estimate and confidence interval will be reported for binary 
endpoints. 
 
Supplementary Analysis Plans (Secondary Endpoints) 
All late AE and the maximum grade for each type of adverse events (including all adverse events 
and those that are possibly, probably or definitely related to study treatments) will be recorded for 
each patient. The frequency tables will be reviewed to determine the patterns. Point estimate and 
confidence interval will be reported for binary endpoints.  All patients meeting the eligibility criteria 
and confirmed by central review who have signed a consent form and have begun any dose of 
treatment will be evaluable for the following secondary endpoints, unless otherwise specified. 
• 
The positive margin resection rate is defined as number of patients achieved R0 versus 
R1/R2 resection during surgery divided by number of evaluable patients. (R0= negative 
margin, R1= microscopically positive margin, R2= macroscopically positive margin).  Point 
estimate and confidence interval of the rate will be reported. 
• 
The histopathologic response rate is defined as number of patients achieved CR or PR 
determined according to histopathologic examination during pre-operative chemo or 
chemoradiotherapy divided by number of evaluable patients.  Point estimate and 
confidence interval of the rate will be reported. 
• 
Time to locoregional recurrence is defined as time from the date of registration to the date 
of the first documented locoregional recurrence. The Kaplan-Meier methods will be used 
to estimate the median time, and event-free rate at specific time points (6 month, 12 
month, etc.). 
• 
Time to distant recurrence is defined as time from the date of registration to the date of 
the first documented distant recurrence. The Kaplan-Meier methods will be used to 
estimate the median time, and event-free rate at specific time points (6 month, 12 month, 
etc.). 
• 
Overall survival is defined as time from the date of registration to the date of the death due 
to all causes. The Kaplan-Meier methods will be used to estimate the median time, and 
event-free rate at specific time points (6 month, 12 month, etc.). 
 
Safety Stopping Rules 
In addition to toxicity feasibility stopping rules, accrual will be temporarily suspended to the study, 
if at any time, we observe events considered at least possibly related to study treatment an 
adverse event with attribute specified as (“possible,”  “probably,”  or  “definite”)  that meet the 
following: 
• 
The rate of treatment-related deaths during treatment, or within the first 60 days following 
completion of treatment, is 2 or more in the first 10 patients, or after 10 patients, 20% or 
more of all treated patients. 
• 
We will also review grade IV and V adverse events deemed “unrelated” or “unlikely to be 
related” to verify their attribution and to monitor the emergence of a previously 
unrecognized treatment-related adverse event 
 
 
X.  DATA REPORTING / REGULATORY CONSIDERATIONS 
 
Study Monitoring 

 
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This study will be monitored by the University of Cincinnati DSMB and IRB.  The PI will be 
responsible for maintaining the clinical protocol and subjects’ study charts, reporting adverse 
events, assuring that consent is obtained and documented, and reporting the status of the trial in 
continuing renewals submitted to their IRB and trail monitoring group(s) as per UC protocol.  
There will be password-protected limited access to the database in order to maintain privacy (See 
Confidentiality below). 
 
Monitoring Plan 
UCCI DSMB will conduct study audits after enrollment of each 10 patients to review subjects’ 
timely and complete enrollment, registration into the electronic database, and follow-up per study 
calendar.  More frequent monitoring will take place as needed. Trial monitoring with subject chart 
and trial binder reviews will be done by the UCCI Clinical Trials office.   
 
Data Entry and Compilation 
Subject data will be documented and stored in the electronic database Oncore, the software and 
infrastructure being supplied by UCCI clinical trials office.  Research Staff (Coordinators, Nurse, 
or Co-Investigators) will enter/scan subject data into Oncore, which will include: 
 
• 
Eligibility or Inclusion/Exclusion Criteria 
• 
Patient Demographics 
• 
Pre-Study Evaluation including H & P, Allergies, and Review of Systems 
• 
Surgical Procedures, with dates and findings (including EUS, biopsy (if needed), seed 
placement, and/or stent (if recommended) 
• 
Scan dates (pancreas protocol CT) 
• 
Treatment planning date 
• 
Pre-Study Labs including hematology, chemistry, and tumor markers (CBC, CMP and CA 
19-9) 
• 
Radiation therapy dates and toxicities reported 
• 
Pre-study chemotherapy records including drugs, doses, and schedules 
• 
Surgery records including pathology reports (pathologic staging, margin status, histology), 
length of hospitalization and postop complications according to Appendix VI.  
• 
Follow-up Evaluations including H&P, Review of Systems, and toxicities 
• 
Follow-up labs and dates 
• 
Completion of QOL questionnaires 
• 
Subject study withdrawal, date, and reason 
• 
Concomitant medications, specifically PPIs and anti-emetics, prescribed per protocol and 
if reportedly taken by subject 
 
Confidentiality 
Study data will be maintained in password protected computer files. Only research personnel 
listed on this protocol will have access to this information. Only the patients unique IDN will be 
used. The patient’s name or other public identifiers will not be included in any information shared 
with other investigators. The study data with identifiers will be kept at in Oncore.  
 
XI.  CORRELATIVE STUDIES 
 
Correlative studies to develop predictive and prognostic information will focus on molecular 
markers of interest in pancreatic cancer.  For all of the markers described below, tissue from both 
pre-treatment biopsies and post-resection specimens will be subjected to immunohistochemical 
(IHC) analysis.  Funding for correlative studies will come from either pending grant applications or 

 
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supported by the UCCI GI Center of Excellence.  
 
Differential expression of these markers correlated with clinical outcomes can provide invaluable 
prognostic data, as well as a basis for future clinical trials with a personalized, molecular profile-
targeted approach.  The markers of interest are: 
 
Hyaluranon- Tumor stroma microenvironment has been very important in pancreas cancer.  The 
interstitial pressure is very high, which limits the diffusion of chemo and blood flow in the tumor10. 
Hyaluronan (HA) is one component of the stroma thought to be responsible for this and HA can 
be evaluated by IHC.  Hyaluronan inhibitor (PEGPH20) is currently under investigation in 
metastatic pancreatic cancer and HA could potentially be used as a radiosenitizer. This would be 
a completely new mechanism of sensitization.  We would plan to evaluate HA concentration by 
IHC, and would consider decreased post-SBRT concentration as a preliminary indicator that 
SBRT has some synergy with HA inhibition warranting further study. 
 
D1R-DA acts as a neurotransmitter in the brain and as a hormone in the periphery. It binds to five 
G-protein-coupled receptors (DAR), grouped by structure and function into D2-like (D2R, D3R 
and D4R) and D1-like (D1R and D5R). The D2R-like are classified by inhibition of cAMP, 
whereas the D1R-like stimulate cAMP. In addition to their distinct distribution and functions within 
the brain, several DAR subtypes are expressed in peripheral tissues, where they participate in the 
control of kidney, cardiovascular, immune and adipose functions; DAR have also been detected 
in some adrenal, ovarian, lung, and colon cancers.  
Drugs that affect DA functions constitute one of the largest classes of pharmaceuticals. They are 
widely used as oral medications for Parkinson’s disease, schizophrenia, hyperprolactinemia, 
renal hypertension, erectile dysfunction and gastrointestinal motility disorders. Among these, 
Fenoldopam (Fen) is of particular interest. Fen is an FDA-approved, selective D1R agonist 
(Kd=2.3 nM) which does not penetrate the brain and does not activate D2R-like or adrenergic 
receptors. Fen is clinically used to treat severe renal hypertension, and has a wide margin of 
safety for normotensive patients, causing only mild hypotension.   
D1R expression in breast cancer: Using rabbit 
monoclonal antibodies (mAb) with high selectivity for 
D1R, Dr Ben-Jonathan’s lab (UC Cancer Biology) has 
discovered robust D1R expression in several BCC. 
They found moderate to strong D1R staining by 
immunohistochemistry in ~30% of 751 primary breast 
carcinomas in tissue microarrys, while D1R was 
undetectable in 30 normal breast tissue samples. D1R 
expression correlated with high tumor grade, size, and 
advanced disease and overall survival. Treatment of 
D1R-expressing BCC with low nM doses of D1R 
agonists reduced cell viability in vitro, induced 
apoptosis, and augmented cell sensitivity to doxorubicin. 
Fen dramatically suppressed the growth of D1R-
expressing breast cancer xenografts in nude mice. We 
plan to evaluate D1R expression by IHC in all pre- and 
post- SBRT paraffin embedded tissue with mAb 
purchased through Epitomics with the assistance of Dr Ben Jonathans lab.  
 
 
A
B
C
Fig 2: Examples of SCCHN primary tumors that stain 
strongly positive (A) or negative (B) by IHC for D1R. C: 
Pie chart showing the D1R-staining distribution pattern 
of 27 SCCHN primary tumors. 

 
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SapC-DOPS  
SapC-DOPS is a nanovesicle technology developed at CCHMC/UC with very promising results in 
pancreas cancer models.  A Phase I trial of this drug will begin at multiple sites including UC in the next 
2-3 months treating all solid tumors.  These vesicles are assembled from saposin C (SapC) and 
dioleylphosphatidylserine (DOPS) bind to phosphatidylserine (PS), preferentially expressed in cancer cell 
surfaces, and are internalized into tumor cells where they induce apoptosis.  Dr. Qi (collaborator in 
Hematology Oncology at UC) has shown that the vesicles target to surface exposed PS and decrease 
cell viability in human pancreatic cancer cells and in subcutaneous as well as orthotopic pancreas 
models.  
 
Synergistic tumor kill between SapC-DOPS and RT has been demonstrated in braincancer cells by Dr. 
Qi and his collaborators.  In addition, Timmerman, et al. have demonstrated in an orthotopic lung cancer 
model that SBRT increases the extracellular expression of PS on tumor vessels from 4% to 26% using 
an antibody to PS called bavituximab.  Moreover in a radiation resistant animal lung model, they 
demonstrated that SBRT + bavituximab produced higher clinical and pathologic response rates than 
either alone.  This raises the possibility that SBRT may increase the effectiveness of SapC-DOPS in 
terms of tumor cell kill in in vivo pancreas models.   
 
We plan to evaluate tumor expression of PS pre- and post-SBRT in human tissue.   In  pre-SBRT core 
biopsies specimens and post-SBRT resection specimens from the above mentioned UC investigator 
initiated “Phase I feasibility study of SBRT in resectable adenocarcinoma of pancreas”, we will plan to 
evaluate the tumor expression of PS by IHC using bavituximab and fluorescently labeled SapC-DOPS .  
These stains and interpretation will be performed by Dr. Jiang Wang in Pathology and Dr. Qi. 
 
 
 
Alternatively spliced Tissue Factor (asTF)  
Tissue Factor (TF) present in blood cells and plasma is referred to as blood-borne or circulating TF.  TF 
has been implicated in the pathogenesis of several chronic disease states, most notably cardiovascular 
disease and cancer.  Full-length TF is an integral membrane protein while alternatively spliced TF can be 
secreted in a free form and features a unique C-terminal domain enabling its selective detection in bio-
specimens.  Recently, asTF was shown to circulate in the blood of metastatic breast cancer patients at 
concentrations exceeding 1 ng/mL (Kocaturk et al, PNAS 2013), and it promoted tumor growth and 
spread in an orthotopic model of pancreatic ductal adenocarcinoma (PDAC, Unruh et al, Int J Cancer, 
2014).  asTF protein acts as a cell agonist driving angiogenesis, cancer cell proliferation, and monocyte 
recruitment via integrin binding.  It is not known whether circulating asTF may contribute to or serve as a 
biomarker in patients with solid cancers including PDAC.  We evaluated circulating asTF in healthy 
subjects and individuals with PDAC. 
 
Samples of platelet poor plasma from 43 subjects were obtained from University of Cincinnati Cancer 
Institute’s Tumor Bank and Diagnostica Stago collections. Blood was drawn into tubes containing acid 
citrate dextrose (PDAC) or sodium citrate (healthy subjects), centrifuged at 3000 rpm for 15 min at 4°C, 
and stored at -80°C until use.  Blinded asTF ELISA was performed on platelet poor plasma samples 
(each in triplicate, 200 ul per well) as per the prototype-tailored procedure (Diagnostica Stago).  Samples 
with asTF concentrations ≥0.2 ng/mL were deemed positive. asTF concentrations are presented as 
mean±SD.  Kruskal-Wallis one-way analysis of variance was used to compare differences in 
concentration levels between the cohorts; Chi-Square and/or Fisher’s exact test were used to compare 
proportions. 
 
asTF protein was detectable in the plasma of 3/19 (15.8%) subjects in the healthy cohort (CORE Set 50, 
George King Bio-Medical) and 20/43 (46.5%) in the PDAC cohort; the proportion of PDAC patients 

 
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positive for asTF was significantly higher compared to that in all other cohorts (p<0.01, Chi-Square test).  
The mean asTF concentrations in the cohorts were as follows: PDAC, 0.403±0.912 ng/mL; healthy 
subjects, 0.169±0.596 ng/mL; the differences between mean asTF levels in the cohorts did not reach 
significance.  Next, we evaluated asTF’s potential as a biomarker to help detect a more aggressive 
PDAC phenotype.  Among the 43 patients with PDAC, 36 were initially deemed resectable and 7 
unresectable due to the presence of metastatic disease as determined by diagnostic screening; following 
exploratory laparoscopic surgery, 11 out of 36 patients initially deemed resectable were deemed 
unresectable due to the presence of metastatic disease.  When the entire PDAC cohort was split into 
bona fide resectable (25) and unresectable (18) sub-cohorts, positivity for asTF was significantly more 
prevalent in the unresectable sub-cohort irrespective of the results of initial evaluation and/or pre-
operative CA19-9 levels (asTF ≥0.2 ng/mL: 13 unresectable and 7 resectable patients; asTF<0.2 ng/mL: 
5 unresectable and 18 resectable patients, p=0.0059, Fisher’s exact test). 
 
Our findings suggest that asTF at levels ≥0.2 ng/mL occurs more frequently in the plasma of patients 
with PDAC compared to healthy subjects.  Further, PDAC patients whose plasma asTF levels were 
equal to or exceeded 0.2 ng/mL had a significantly lower chance to qualify for tumor resection, 
irrespective of initial pre-surgical diagnostic evaluation.  asTF may thus comprise a novel marker of 
aggressive PDAC phenotype with potential utility in patient stratification, warranting prospective 
evaluation of larger PDAC patient cohorts. 
 
Proposed research: prospective evaluation of asTF levels in circulation of patient with PDAC at 3 
time points pre / post-SBRT (time point 0-14 days before surgery) and post-operative.  Blood will 
be drawn in 3 ml sodium citrate tubes, ~1.5 ml of platelet poor plasma isolated, frozen until use, and 
assayed for asTF using ELISA as described above. We hypothesize that asTF levels will i) drop post-
SBRT, ii) further drop post-resection, and iii) rise either concomitantly or shortly before recurrence.  We 
also hypothesize that higher asTF levels at the onset and/or during the study will positively correlate with 
more aggressive disease and, consequently, poorer response to treatment. 
 
 
XII.  MEASUREMENT OF EFFECT 
 
Anti-tumor Effect 
Patients will be evaluated for anti-tumor effect by follow-up imaging (pancreas protocol CT and/or 
PET-CT imaging) as outlined above. All subsequent scans (post-treatment) will be compared to 
the same pretreatment CT that was used in conjunction with radiation treatment planning.  
Patients will be evaluable for toxicity and evaluable for objective response at the follow-up 
intervals specified above. 
 
Disease Parameters 
Pancreatic tumor response will be based upon standard radiographic criteria for the treated lesion 
and will be prospectively recorded in the UC secure database. Radiographic response of the 
pancreatic tumor by diagnostic CT scans will be defined according to RECIST criteria as 
described below: 
 
• 
CR = complete disappearance of index lesion 
• 
PR = at least 30% decrease in the longest diameter of the index lesion  
• 
PD = more than 20% increase in the longest diameter of the index lesion  
• 
SD = does not meet criteria for PR or PD 
 
Local tumor progression will be defined as >=20% increased size on CT scan compared to a CT 

 
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scan from prior to treatment. Distant progression will be defined as any new tumor found outside 
of the pancreas or periampullary region on CT scan. Local and/or distant progression will be 
evaluated by both PET/CT (if available) and CT scan as deemed by treating physician.  
 
Methods for Evaluation of Measurable Disease 
Pancreas protocol CT scans (biphasic imaging, 1.25 mm cuts) and/or FDG PET-CT scans 
(optional and if recommended by the treating physician) will be obtained at all follow-up intervals 
as described in the treatment calendar. 
 
XIII.  RESPONSE CRITERIA 
 
Evaluation of Target Lesions 
Patients’ responses to therapy will also be evaluated clinically after completion of their Linac 
based SBRT. The following are clinical definitions for response: 
 
• 
CR = complete alleviation of pain or other symptoms thought to be related to the index 
lesion 
• 
PR = improvement, but not complete elimination, of pain or other symptoms thought to be 
related to the index lesion 
• 
PD = worsening of pain or other symptoms thought to be related to the index lesion SD = 
does not meet criteria for PR or PD 
• 
Radiographic response will be defined as outlined in section 11.1.2.  
 
Evaluation of Non-Target Lesions 
Standard radiographic criteria will be utilized for non-target lesions.  Any disease outside of the 
pancreas region will be considered metastatic disease. If possible a biopsy should be obtained to 
confirm metastasis. 
 
Evaluation of Best Overall Response 
This will be based upon the response of the treated lesion as described above. 
 
Duration of Response 
The criteria for overall response will be the time between treatment and first sign of local 
progression or development of new metastatic disease. 
 
Response Review 
All responses will be reviewed independently by a board certified radiologist at the study’s 
completion. Each image will be reviewed by the PI. Simultaneous review of the patient’s chart will 
also occur at this time.  
 
 
 
 
 
 
 
 
 
 
 
 

 
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APPENDIX I 
STUDY CALENDAR 
 
Pre-Study Pre-SBRT8 
SBRT Treatment9,10 
Follow-Up 5 
(Post-Radiation Treatment) 
4-6 
weeks 
4 
mos 
63 
mos 
9 
mos 
123 
mos 
Yrs 2-5 
Q 3-6 mos 
Initial Consult 
X 
 
Demographics 
X 
 
History / Physical Exam 
X 
 
X 
X 
X 
X 
X 
X 
Informed consent 
X 
 
 
 
 
 
 
 
Biopsy 
(confirmed adenocarcinoma) 
X 
 
 
 
 
 
 
 
Labs: CBC, CMP, CA19-9 
 
X6 
X 
X 
X 
X 
X 
X 
Post-op complication 
assessment (appendix 6) 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Negative Pregnancy Test7 
 
X 
 
 
 
 
 
 
Seed Placement 
(EUS, CT, intraoperatively) 
 
X 
 
 
 
 
 
 
Simulation Scan 
 
X 
 
 
 
 
 
 
Radiologic Evaluation (CT) 
 
X 
X2 
X 
X 
X 
X 
X 
QoL Questionnaire 
 
X 
X 
X4 
X 
X4 
X 
X 
AE Evaluation 
X 
 
X 
X 
X 
X 
X 
X 
Research tubes 
 
X 
 
X11 
 
 
 
 
 
1 - CT pancreas or chest/abdomen/pelvis, as per treating physician, required pre- and post-SBRT. 
2 - If being reevaluated for resection, scans will be conducted at 4-6 weeks or as determined necessary by 
treating physician. 
3 - It is preferred that patients have the 6MFU and 12MFU evaluation and imaging at the treating institution. 
Other evaluations may be done at a local center however records must be submitted to SBRT treating facility. 
4 - QoL questionnaires may be completed and returned by mail if preferred. 
5 - Follow-up appointments have a +/- 30 day tolerance window. (ex. 6MFU may occur between 5-7 months) 
6 - Pre-SBRT labs should be done within 2 weeks prior to treatment. 
7 - Pregnancy test by urine or serum, for women who are not post-menopausal as defined in Appendix III. 
8 - Pre-SBRT procedures should be completed within 45 days of beginning treatment. 
9 - It is recommended that patients discontinue any chemotherapy one week prior to SBRT   
10 - Ideally all 5 fractions should be delivered Monday through Friday; however, treatment may be delivered over 
2 weeks, as long as the patient receives at least 2 fractions per week. 
11- Pre-surgery 

 
UCCI-GI-002 
Amendment 4 
Page 35  
4/15/2016 
 
APPENDIX II 
 
EORTC QLQ - 30 
 
We are interested in some things about you and your health.  Please answer all the questions yourself by selecting the 
number that best applies to you.  There are no “right” or “wrong” answers.  The information that you provide will remain 
strictly confidential. 
 
 
Not 
at 
All 
A 
Little 
Quite 
a Bit 
Very 
Much 
Do you have any trouble doing strenuous activities, like carrying a heavy 
shopping bag or a suit case? 
1 
2 
3 
4 
Do you have any trouble taking a LONG walk? 
1 
2 
3 
4 
Do you have any trouble taking a SHORT walk outside of the house? 
1 
2 
3 
4 
Do you need to stay in bed or a chair during the day? 
1 
2 
3 
4 
Do you need help eating, dressing, washing yourself or using the toilet? 
1 
2 
3 
4 
During the past week: 
Were you limited in doing either your work or other daily activities? 
1 
2 
3 
4 
Were you limited in persuing your hobbies or other leisure time activities? 
1 
2 
3 
4 
Were you short of breath? 
1 
2 
3 
4 
Have you had pain? 
1 
2 
3 
4 
Did you need to rest? 
1 
2 
3 
4 
Have you had trouble sleeping? 
1 
2 
3 
4 
Have you felt weak? 
1 
2 
3 
4 
Have you lacked appetite? 
1 
2 
3 
4 
Have you felt nauseated? 
1 
2 
3 
4 
Have you vomited? 
1 
2 
3 
4 
Have you been constipated? 
1 
2 
3 
4 
Have you had diarrhea? 
1 
2 
3 
4 

 
UCCI-GI-002 
Amendment 4 
Page 36  
4/15/2016 
 
Were you tired? 
1 
2 
3 
4 
 
Not 
at 
All 
A 
Little 
Quite 
a Bit 
Very 
Much 
Did pain interfere with your daily activities? 
1 
2 
3 
4 
Have you had difficulty in concentrating on things, like reading a newspaper or 
watching television? 
1 
2 
3 
4 
Did you feel tense? 
1 
2 
3 
4 
Did you worry? 
1 
2 
3 
4 
Did you feel irritable? 
1 
2 
3 
4 
Did you feel depressed? 
1 
2 
3 
4 
Have you had difficulty remembering things? 
1 
2 
3 
4 
Has your physical condition or medical treatment interfered with your FAMILY 
life? 
1 
2 
3 
4 
Has your physical condition or medical treatment interfered with your SOCIAL 
activities? 
1 
2 
3 
4 
Has your physical condition or medical treatment caused you financial 
difficulties? 
1 
2 
3 
4 
 
 
For the following questions please select the number between 1 (Very Poor) and 7 (Excellent) that best applies to you. 
 
 
 
 
 
 
 
 
 
           
 Very Poor 
                Excellent 
How would you rate your overall HEALTH during the past week? 
1 
2 
3 
4 
5 
6 
7 
How would you rate your overall QUALITY OF LIFE during the past week? 
1 
2 
3 
4 
5 
6 
7 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
UCCI-GI-002 
Amendment 4 
Page 37  
4/15/2016 
 
 
 
 
 
 
 
 
 
 
 
APPENDIX III 
 
 
 
 
EORTC QLQ – PAN26 
 
Patients sometimes report that they have the following symptoms or problems.  Please indicate the extent to which you have 
experienced these symptoms or problems DURING THE PAST WEEK.  Please answer by checking the number that best applies 
to you. 
 
 
Not 
at 
All 
A 
Little 
Quite 
a Bit 
Very 
Much 
Have you had abdominal discomfort? 
1 
2 
3 
4 
Did you have a bloated feeling in your abdomen? 
1 
2 
3 
4 
Have you had back pain? 
1 
2 
3 
4 
Did you have pain during the night? 
1 
2 
3 
4 
Did you find it uncomfortable in certain positions (e.g. lying down)? 
1 
2 
3 
4 
Were you restricted in the TYPES of food you can eat as a result  
of your disease or treatment? 
1 
2 
3 
4 
Were you restricted in the AMOUNT of food you can eat as a result  
of your disease or treatment? 
1 
2 
3 
4 
Did food or drink taste different from usual? 
1 
2 
3 
4 
Have you had indigestion? 
1 
2 
3 
4 
Were you bothered by gas (flatulence)? 
1 
2 
3 
4 
Have you worried about your weight being too low? 
1 
2 
3 
4 
Did you feel weak in your arms and legs? 
1 
2 
3 
4 
Did you have dry mouth? 
1 
2 
3 
4 
Have you had itching? 
1 
2 
3 
4 

 
UCCI-GI-002 
Amendment 4 
Page 38  
4/15/2016 
 
To what extent was your skin yellow? 
1 
2 
3 
4 
Did you have frequent bowel movements? 
1 
2 
3 
4 
Did you feel the urge to move your bowels quickly? 
1 
2 
3 
4 
Have you felt physically less attractive as a result of your disease and treatment? 
1 
2 
3 
4 
 
Not 
at 
All 
A 
Little 
Quite 
a Bit 
Very 
Much 
Have you been dissatisfied with your body? 
1 
2 
3 
4 
To what extent have you been troubled with side-effects from your treatment? 
1 
2 
3 
4 
Were you worried about your health in the future? 
1 
2 
3 
4 
Were you limited in planning activities, for example meeting friends, in advance? 
1 
2 
3 
4 
Have you received adequate support from your health care professionals? 
1 
2 
3 
4 
Has the information given about your physical condition and treatment been 
adequate? 
1 
2 
3 
4 
Have you felt less interest in sex? 
1 
2 
3 
4 
Have you felt less sexual enjoyment? 
1 
2 
3 
4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
UCCI-GI-002 
Amendment 4 
Page 39  
4/15/2016 
 
APPENDIX IV 
 
Karnofsky Performance Status 
 
Score 
 Description 
100 
 Normal, no complaints, no evidence of disease. 
90 
 Able to carry on normal activity; minor signs or symptoms of disease. 
80 
 Normal activity with effort; some signs or symptoms of disease. 
70 
 Cares for self, unable to carry on normal activity or do active work. 
60 
 Requires occasional assistance, but is able to care for most of his/her needs. 
50 
 Requires considerable assistance and frequent medical care. 
40 
 Disabled, requires special care and assistance. 
30 
 Severely disabled, hospitalization indicated. Death not imminent. 
20 
 Very sick, hospitalization indicated. Death not imminent. 
10 
 Moribund, fatal processes progressing rapidly. 

 
UCCI-GI-002 
Amendment 4 
Page 40  
4/15/2016 
 
APPENDIX V 
 
Definition of Menopausal Status 
 
Menopausal status will be defined according to the following criteria: 
 
Post-menopausal: 
 
• 
Woman 60 years of age or older 
• 
Woman aged 45-59 years with spontaneous cessation of menses for at least 12 months prior to 
registration 
• 
Woman aged 45-59 years with cessation of menses for less than 12 months prior to 
• 
registration AND an FSH level in the postmenopausal range (or >34.4 IU/L if institutional range is 
not available) 
• 
Woman aged 45-59 years on hormone replacement therapy who have discontinued hormone 
replacement therapy at diagnosis of breast carcinoma and have an FSH level in the 
postmenopausal range according to institutional/laboratory standards (or 34.4IU/L if the 
institutional range is not available) 
• 
Prior bilateral oophorectomy 
• 
Woman younger than 60 years of age who have had a prior hysterectomy (without bilateral 
oophorectomy) AND who have an FSH level in the postmenopausal range (or >34.4 IU/L if 
institutional range is not available) 
 
Pre- or peri-menopausal:   
 
• 
Not meeting definition for postmenopausal as outlined above. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
UCCI-GI-002 
Amendment 4 
Page 41  
4/15/2016