MR Guided Phase II Radiotherapy Dose Escalation in Unresectable Non-metastatic Pancreatic Cancer
Phase: PHASE2
Conditions: Unresectable Pancreatic Cancer
Sponsor: Medical College of Wisconsin

Official Title:  MR Guided Phase II Radiotherapy Dose Escalation in Unresectable Non-
Metastatic Pancreatic Cancer 
 
NCT Number:  NCT01972919 
 
Document Date:  02/21/2023 

IIT Erickson Pancreas v 14 02/21/2023 
 
MR-guided Phase II Radiotherapy Dose Escalation in 
Unresectable Non-metastatic Pancreatic Cancer
 
Study Chairs 
 
 
Principal Investigator/Radiation Oncology  
Beth Erickson MD, FACR, FASTRO, FABS 
Professor 
Radiation Oncology
9200 W. Wisconsin Ave. 
Milwaukee, WI  53226 
Phone: 414-805-4460 
Fax: 414-805-4369 
Pager: 414-557-9418 
Email: berickson@mcw.edu 
 
Radiation Oncology
William Hall, MD 
 
Medical Oncology  
Ben George, MD 
James Thomas, MD 
Mandana Kamgar, MD 
Sakti Chakrabarti, MD
Aditya Shreenivas, MD 
Thomas Giever, DO, MBA
 
Diagnostic Radiology 
Mark Hohenwalter, MD
Paul Knechtges, MD 
Radiation Oncology Physics  
Allen Li, PhD 
Eric Paulson, PhD  
An Tai, PhD   
Phil Prior, PhD 
Xinfeng Chen, PhD
 
Surgical Oncology  
Kathleen Christians, MD
Douglas Evans, MD
T. Clark Gamblin, MD, MS, MBA 
Susan Tsai, MD, MHS 
Callisia Clark, MD, MS  
                                                                          
 
Statistician
Mei-Jie Zhang, PhD
 
 
Document History 
 
 
Version: 14 02/21/2023 
Funded by the Department of Radiation Oncology

 
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Table of Contents
Schema ................................................................................................................................................................................... 4
1.0 INTRODUCTION...............................................................................................................................................................6
1.1 Rationale for Selected Approach and Trial Design ........................................................................................................... 6
2.0 OBJECTIVES..................................................................................................................................................................18
2.1 Primary Objective ........................................................................................................................................................ 18
2.2 Secondary Objectives..................................................................................................................................................18
3.0 PATIENT SELECTION .................................................................................................................................................... 18
3.1 Conditions for Patient Eligibility...................................................................................................................................18
3.2 Conditions for Patient Ineligibility ................................................................................................................................ 20
4.0 REGISTRATION PROCEDURES ................................................................................................................................... 21
5.0 RADIATION THERAPY ................................................................................................................................................... 21
5.1 Localization, Simulation, and Immobilization............................................................................................................... 21
5.2 Target and Critical Structure Volumes for Treatment Planning ................................................................................... 23
5.3 Dose Specifications and Dose Volume Constraints .................................................................................................... 23
5.4 Treatment Delivery ...................................................................................................................................................... 25
5.5 Documentation Requirements ..................................................................................................................................... 26
5.6 Compliance Criteria ..................................................................................................................................................... 26
5.7 Radiation Therapy QA and Reviews ........................................................................................................................... 28
5.8 Radiation Therapy Adverse Events ............................................................................................................................. 29
5.9 Radiation Therapy Adverse Event Reporting .............................................................................................................. 29
6.0 DRUG THERAPY ............................................................................................................................................................ 29
6.1 Treatment .................................................................................................................................................................... 29
6.2 Gemcitabine (HCI) Agent Information ......................................................................................................................... 30
6.3 Capecitabine Agent Information .................................................................................................................................. 31
6.4 Adverse Events ........................................................................................................................................................... 32
6.5 Dose Modifications ......................................................................................................................................................32
6.6 Adverse Events ........................................................................................................................................................... 34
7.0 OTHER THERAPY..........................................................................................................................................................34
7.1 Permitted Supportive Therapy ..................................................................................................................................... 34
7.2 Non-Permitted Supportive Therapy ............................................................................................................................. 35
8.0 PATIENT ASSESSMENTS ............................................................................................................................................. 35
8.1 Study Parameters ........................................................................................................................................................ 35
8.2 Evaluation During Treatment ....................................................................................................................................... 35
8.3 Measurement of Response ......................................................................................................................................... 35
8.4 Criteria for Discontinuationo of Protocol Treatment .................................................................................................... 37
8.5 Summary of Dosimetry Digital Data ............................................................................................................................ 37
9.0 TISSUE/SPECIMENT ANALYSIS .................................................................................................................................. 38
10.0 STATISTICAL CONSIDERATIONS .............................................................................................................................. 38
10.1 Study Endpoints ........................................................................................................................................................ 38
10.2 Sample Size .............................................................................................................................................................. 38

 
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10.3 Analysis Plan ............................................................................................................................................................. 40
REFERENCES ...................................................................................................................................................................... 42
APPENDIX 1 NCCN CRITERIA ............................................................................................................................................ 50
APPENDIX II STUDY PARAMETER TABLE ........................................................................................................................ 51
APPENDIX III ZUBROD PERFORMANCE SCALE .............................................................................................................. 52
APPENDIX IV AJCC STAGING SYSTEM ............................................................................................................................ 53
APPENDIX V DUAL PHASE PANCREATIC IMAGING PROTOCOL .................................................................................. 54
APPENDIX VI DUODENAL/STOMACH ANATOMY ............................................................................................................. 55
APPENDIX VII GLOSSARY OF TERMS .............................................................................................................................. 57
 

 
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Phase II Radiotherapy Dose Escalation in
Unresectable Non-metastatic Pancreatic Cancer
Schema:
All patients will receive radiation to doses >50.4 Gy, five days per week over six to seven weeks. The 
Planning Target Volume (PTV) (PTV low dose) will include the pancreatic head or body or tail, where 
the tumor originated, as well as the major associated blood vessels and any suspicious nodes. This 
PTV will be treated with traditional dose per fraction radiation. The MR-defined tumor (PTV boost) will 
be treated with a simultaneous integrated boost (SIB) to a higher dose per fraction and will get the 
escalated dose. Patients will be treated with 28, 29, 30, or 31 fractions dependent on meeting the 
normal tissue dose constraints as shown in the table below. Treatment planning will be done to 
achieve the highest dose plan (31 fractions) if the normal tissue dose constraints can be met. If the 
normal tissue dose constraints are not met, the dose will be adjusted down incrementally from 31 to 
30 to 29 to 28 fractions until the dose constraints are met.  
Fractions 
28 
fractions 
29  
fractions 
30 
fractions 
31 
fractions 
PTVlow dose 
28 x 1.8Gy 
50.4 Gy 
29 
x 
1.75Gy 
50.75Gy 
30           x 
1.70Gy
51 Gy 
31 
x 
1.65Gy 
51.15Gy 
PTVboost(SIB) 28           x 
2.25 Gy 
63 Gy 
29 
x
 2.25Gy 
65.25Gy 
30          x 
2.25Gy
67.5 Gy 
31 
x 
2.25Gy 
69.75Gy 
 Dose level depends on duodenal, small bowel and gastric doses 
 Chemotherapy: concurrent Gemcitabine or Capecitabine 
Patient Population:  (See Section 3.0 for Eligibility)  
Pathologically confirmed (histologic or cytologic), unresectable non-metastatic adenocarcinoma of the 
pancreas (Appendix I). Patients must have received at least four months of any type of systemic 
chemotherapy prior to enrolling in the trial. Any type or duration of prior chemotherapy beyond four
months is acceptable as long as there is no evidence of distant metastases. Patients may have 
responding, stable, or locally progressive disease as long as there is not definite metastatic disease. 
Patients with bulky tumors (> 7cm) may not be eligible if the MR-defined SIB PTV volume is too large 
(>400 cc). Additionally, patients with a suboptimal performance status will not be considered for the 
study (Zubrod Performance Status < 0–1), A minimum of two weeks is required between the last 
cycle of chemotherapy and the first fraction of radiation. 
Patients must be able to undergo MR scans for baseline evaluation, radiation planning, and follow-up. 

 
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Required Sample Size:  23 patients

 
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1.0
INTRODUCTION 
Pancreatic cancer is the fourth leading cause of cancer-related death in the United States. 
Despite aggressive combined modality treatment approaches, the overall five-year survival 
remains less than 7%. (Sener 1999; Herman 2010; Cooke 2010; Siegel  2015) Although 
surgery is historically the only curative option, the majority of patients have unresectable or 
metastatic disease at presentation.  
Conventional treatment for locally advanced pancreatic cancer is unsatisfactory. The 
emergence of more effective chemotherapy may help to decrease the risk of failure outside of 
the pancreas and make radiation more pivotal in contributing to cure. 
 
The advent of contemporary advanced radiation therapy technology allows for escalation of 
radiation dose to levels previously unobtainable. (Ben-Josef 2004; Ben-Josef 2012) Select 
patients with unresectable pancreatic cancer may be curable with high-dose chemoradiation if 
they do not develop metastatic disease.  
 
1.1 
Rationale for Selected Approach and Trial Design 
1.1.1 Locally Advanced Pancreatic Cancer
Of the 48,960 patients diagnosed with pancreatic carcinoma in the United States from 2007 to 
2011, approximately 40% presented with locally advanced disease. (Jemal 2015) These 
patients have pancreatic tumors that are surgically unresectable due to encasement or 
occlusion of the superior mesenteric vein (SMV), SMV/portal vein confluence, or direct 
involvement of the superior mesenteric artery (SMA), celiac axis, inferior vena cava, or aorta. 
These patients are now approached initially with systemic chemotherapy and radiation is used 
selectively based on response to chemotherapy and performance status. (Huguet 2007)
 
1.1.2 Chemoradiation for Locally Advanced Pancreatic Cancer 
The Mayo Clinic had a randomized trial in the 1960s in which 64 patients with surgically staged
locally unresectable, non-metastatic pancreatic adenocarcinoma received 35 to 40 Gy of 
radiation and concurrent fluorouracil (5-FU/RT) versus radiation alone. A significant survival 
advantage was seen for patients receiving 5-FU/RT (10.4 months vs. 6.3 months, 
respectively). (Moertel 1969) The Gastrointestinal Tumor Study Group (GITSG) followed with a 
study of 194 patients comparing RT alone (60 Gy split course) to 5FU (bolus)/RT (40 Gy or 60 

 
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Gy split course) and maintenance 5-FU. A survival benefit was demonstrated with the 
combined modality arms (Moertel 1981). The RT alone arm closed early due to inferior 
survival. The one-year survival rates in the two CRT arms were 38 and 36%, respectively vs.
11% in the RT arm. (Moertel 1981) 
A follow-up GITSG trial compared chemotherapy alone to chemoradiotherapy in surgically 
confirmed unresectable tumors. Forty-three patients were randomized to receive combination 
streptozocin, mitomycin, and 5-FU (SMF) chemotherapy or 5-FU (bolus)/XRT (54 Gy) followed 
by adjuvant SMF chemotherapy. The chemoradiotherapy arm demonstrated a significant 
survival advantage over the chemotherapy-alone arm (one-year survival, 41% vs. 19%) 
(GITSG 1998). 
 
Contrastingly, the Eastern Cooperative Oncology Group (ECOG) reported no benefit to 
chemoradiotherapy versus chemotherapy only. (Klaassen 1985) In the ECOG study, patients 
with unresectable, non-metastatic pancreatic or gastric adenocarcinoma were randomly 
assigned to receive either 5-FU chemotherapy alone or 40 Gy external beam RT with 
concurrent bolus 5-FU on week. Of the 91 pancreas patients, no survival difference was 
observed between the two groups (median survival, 8.2 vs. 8.3 months). (Klaassen 1985) The 
subsequent ECOG trial E4201, however, demonstrated a survival benefit for gemcitabine and 
concurrent radiation as compared to gemcitabine alone. (Loehrer 2008; Loehrer 2011) 
 
Continuous-infusion 5-FU allows for increased cumulative drug dose and a more protracted 
radiosensitization relative to bolus 5-FU. Phase I and phase II trials have been performed in 
pancreatic cancer, showing that the use of infusional 5-FU is without excessive treatment-
related toxicity and is effective. (Whittington 1995; Bo 2001; Osti 2001) Continuous oral dosing 
of capecitabine simulates a continuous 5-FU infusion. (Ben-Josef 2004; Vaishampayan 2002) 
Phase II studies of capecitabine/RT appear to have equivalent outcomes to continuous 
infusion 5-FU. (Dunst 2002).  
 
The Groupe Cooperateur Multidisciplinaire en Oncologie (GERCOR) retrospectively evaluated 
128 patients with locally advanced pancreatic cancer who were prospectively enrolled on 
multiple clinical trials and had received chemotherapy for at least three months. In patients 
without disease progression, the investigator determined whether to continue chemotherapy or 
proceed with chemoradiation to 55 Gy with concurrent infusion 5-FU. The groups were 

 
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balanced for initial characteristics and induction chemotherapy. In the group receiving CRT vs.
chemotherapy alone, the progression and median overall survival times were 10.8 vs. 7.4 
months and 15.0 vs.11.7 months. (Huguet 2007)
 
1.1.3 Induction Chemotherapy  
Induction chemotherapy is favored prior to chemoradiation to provide early optimal systemic 
treatment and also to select patients most likely to benefit from chemoradiation. (Krishnan 
2007; Huguet 2007) Previous RTOG studies, such as RTOG 0411, have shown no increase in 
toxicity during chemoradiation when induction chemotherapy is first administered.  
Most induction chemotherapy for pancreatic cancer has consisted of gemcitabine-based 
regimens. (Krishnan 2007, Varadhachary 2008) The LAP 07 trial evaluated gemcitabine alone 
versus gemcitabine followed by radiation in patients with locally advanced pancreatic cancer. 
(Hammel, 2013) In this trial, 442 patients were first randomized to gemcitabine alone or 
gemcitabine plus erlotinib for four months. Patients without progression (60%) were then 
randomized to two additional months of chemotherapy or chemoradiation (54 Gy). There was 
no improvement in survival with the addition of radiation following gemcitabine for patients with 
locally advanced pancreatic cancer. Criticisms of this trial are that the radiation doses used 
were low in comparison to single institutional data. In contrast, a phase III trial by ECOG 
showed a survival advantage to the combination of radiotherapy and gemcitabine over 
gemcitabine alone. (Loehrer 2011) The study was closed early because of slow accrual; 
however, in the 74 patients enrolled, median survival improved from 9.2 to 11.1 months with 
the addition of radiation (p=0.017). These results, together with the John Hopkins University’s 
rapid autopsy series revealing that uncontrolled local growth, rather than distant metastatic 
disease, is the cause of death in 30% of patients (Iacobuzio-Donahue 2009), confirm the 
premise that survival may be improved in select patients with unresectable pancreatic cancer 
with more intensified local therapy. 
 
 More recently, a phase III clinical trial has demonstrated that the aggressive multidrug 
regimen FOLFIRINOX (fluorouracil, oxaliplatin, leucovorin and irinotecan) was statistically 
significantly superior to gemcitabine with respect to response rate (31.6% vs. 9.4%), 
progression-free survival (6.4 months vs. 3.3 months), and overall survival (11.1 months vs. 
6.8 months) (Conroy 2011). This drug combination is now used in the neoadjuvant setting for 
patients with resectable and borderline resectable pancreas cancer. (Christians 2014) 
 

 
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1.1.4 Dose Escalation in Pancreatic Cancer
Despite combinations of chemotherapy and radiation, local control, as well as distant control, 
continues to be a challenge for patients with locally advanced unresectable pancreatic cancer. 
Local progression occurred at the site of failure in 58% of the patients treated to 60 Gy in the 
GITSG study. (Moertel 1981) The Mayo Clinic has also demonstrated a high local failure rate 
of 70% in patients with unresectable pancreatic cancer treated to 40 to 60 Gy. (Roldan Cancer 
1988) 
 
A study at Thomas Jefferson University attempted to escalate the dose to 70 Gy with 
conventionally fractionated external beam irradiation with or without chemotherapy but there 
was still a high rate of local failure of 78%. This study, however, was done before the era of 
imaged-based technology for treatment planning and delivery. (Whittington 1984; Dobelbower 
1980) Other studies have explored dose escalation for pancreatic cancer. (Hasard 2009; 
Brunner 2010; Gutt 2010; Ben-Josef 2012) 
 
An analysis of recently published data was performed to assess the usefulness of dose 
escalation. (Moraru 2014) The results of trials with various dose fractionation schemes and 
several chemotherapeutic agents and schedules are summarized in Table 1. Patient 
participation required histologic/cytologic confirmation of unresectable pancreatic 
adenocarcinoma without distant metastases. Only results published after 1997 were included.  
Studies not reporting tumor response or those combining conventional radiation schedules 
with a large boost dose were excluded. Radiation treatment was usually combined with 
different chemotherapy treatments, yet due to the lack of sufficient studies for separate 
analysis, no distinction was made between the various agents.   
 
In order to properly compare the data, a biologically equivalent dose (BED) was calculated for 
each trial based on the fractionation scheme and treatment duration, using estimates for the 
radiobiological parameters. (Qi 2006) Assessment of the median survival data as a function of 
the equivalent dose administered yielded no discernible correlation. This coincides with clinical 
experience that no treatment modality attempted thus far has proven distinctive in improving 
patient outcome.  
  
Although the clinical results indicate no survival advantage with increasing the radiation dose, 
it is worthwhile to examine the response to treatment, since increased tumor control is 

 
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recognized as beneficial in terms of palliation and quality of life, even in the absence of a 
curative outcome. Some of these studies, however, may not have had optimal chemotherapy 
to control distant disease. Consequently, we analyzed the tumor response reported as a 
function of the radiation treatment, shown in Figure 1, where the clinical assessments were 
obtained from CT analysis or MRI in a few cases. These include the probability of complete 
responses (CR) and partial responses (PR). The former entails the disappearance of all target 
lesions, while the latter is defined according to the WHO Handbook (Miller 1981) and RECIST 
criteria. (Therasse 2000) For the analysis, we have differentiated tumor control as the fraction 
of all patients exhibiting CR, PR, and SD, while tumor response comprised of only those with 
CR and PR.   
 
To quantify the added advantage for increasing dose, we utilized a modified linear quadratic 
(MLQ) model (Tai 2008) 
2 fit to the response data from conventional and high 
dose/fraction treatment. The extracted radiobiological parameters were used to calculate the 
BED. The results reveal that there is a benefit of increased tumor response with higher dose 
radiation, as illustrated in Figure 1. According to the fit, the standard fractionation of 50.4 Gy 
given in 28 fractions (1.8 Gy/fx) gives roughly a 10% tumor response. Using 2.25 Gy per 
fraction, a 37% response is expected for a total dose of 65.3 Gy administered in 29 fractions, 
43% for 69.8 Gy in 31 fractions and 46% for 74.3 Gy in 33 fractions, pointing to good 
improvement in tumor response with dose escalation. For 70 Gy in 28 fractions (2.5 Gy/fx), a 
54% tumor response is expected. Normal tissue complications, however, at these higher 
doses, need to be carefully considered. 
 
 
Study  
Group
Dose
(Gy) 
Dose/Fx 
(Gy) 
No. of 
Patients
1 Yr. Survival 
(%) 
Response 
(%) 
Chemotherapy  
Regimen 
Conventional
Ishii, 1997 ()
50.4
1.8
20
41.8 
10.0 
5-FU        
Ceha, 2000)
72.0
2.0
44
47.0 
27.0 
-
Andre, 2000 ()
45.0
1.8
32
31.0 
16.0 
Cisplatin, 5-FU
Kornek, 2001 () 
45.0
1.8
15
13.3 
6.0 
Mitomycin C, GEM 
Boz, 2001 () 
59.4
1.8
42
26.0 
23.0 
5-FU
Ashamalla, 2003 () 
63.4
1.1
20
56.0 
30.0 
Paclitaxel 
Li, 2003 ()
52.4
1.8
34
43.5 
31.3 
5-FU, GEM 
Okusaka, 2004 () 
50.4
1.8
42
28.0 
21.0 
GEM 
Morganti, 2004 (1)
39.6
1.8
15
 
6.7 
5-FU
 
50.4
1.8
15
31.3* 
13.3 
5-FU
 
59.4
1.8
20
 
5.0 
5-FU
Cohen, 2005 () 
59.4
1.8
104
20.0 
8.0 
Mitomycin C, 5-FU 
Tsujie, 2006 ()
45.0
1.5
20
40.0 
35.0 
Cisplatin, 5-FU
Wilkowski, 2006 () 
45.0
1.8
32
67.2 
62.6 
5-FU, GEM 
Murphy, 2007 () 
36.0
2.4
74
47.0 
15.0 
GEM 
Saif, 2007 () 
50.4
1.8
20
58.0 
20.0 
Capecitabine
Small, 2008 ()
36.0
2.4
39
47.0  
5.1 
GEM 
Crane, 2009 ( 
50.4
1.8
82
47.0 
26.0 
Bevacizumab, Capecitabine 

 
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Study  
Group
Dose
(Gy) 
Dose/Fx 
(Gy) 
No. of 
Patients
1 Yr. Survival 
(%) 
Response 
(%) 
Chemotherapy  
Regimen 
Sudo, 2011 ()
50.4
1.8
34
70.6
12.0
Oral S-1, GEM
SBRT
De Lange, 2002 ()
24.0
8.0
24
46.0
29.2
GEM
Mahadevan,2010() 
29.3
9.8
36
50.0 
61.0 
GEM 
Polistina, 2010  (27)
30.0
10.0
23
39.1 
69.6 
GEM 
TABLE 1:  Recent clinical data on pancreatic cancer using combined modalities of radiation therapy and chemotherapy. 
Note:  Response includes reported complete responses (CR) + partial responses (PR). 
*- averaged over entire trial population. 
 
 
FIGURE 1:  Tumor response vs biologically equivalent dose for radiotherapy treatment of 
unresectable pancreatic cancer.                                           
 
1.1.5 IMRT for Unresectable Pancreatic Cancer 
Intensity-modulated radiation therapy (IMRT) is a technique that allows for a very conformal 
dose distribution to established targets with favorable sparing of adjacent critical organs when 
compared to most 3D conformal plans. Studies in the literature confirm the feasibility of IMRT 
in the upper abdomen. (Ben-Josef 2004; Ben-Josef  2012; Fuss 2005; Milano 2004; Yovino 
2011) The use of IMRT as a boost (Brown 2006) and throughout treatment has been 
described. Inherently, IMRT may be superior to 3D conformal radiation when delivering high 
doses to the designated targets while attempting to spare immediately adjacent critical organs, 
particularly if motion is minimized. Sparing of the GI tract is particularly important, especially in 
the setting of dose escalation. (Yovino 2011; Wood 2010). IMRT was used in a phase I/II trial 
(Ben-Josef 2012) at the University of Michigan, to escalate the dose from 50 to 60 Gy in 25 

 
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fractions delivered concurrently with full-dose gemcitabine (1000 mg/m2 weekly on weeks 1, 2, 
4, and 5 of radiotherapy). There was no elective lymph node irradiation and the Gross Tumor 
Volume (GTV), defined on CT, was expanded by 0.5 cm to form the Clinical Target Volume
(CTV). The trial accrued 50 patients and established that high-dose radiotherapy (55 Gy in 25 
fractions) can be delivered safely with concurrent full-dose gemcitabine, with the use of IMRT. 
The rate of severe toxicity (24%) observed at this dose compares favorably with toxicities 
reported with other contemporary regimens. The median and two-year survival in this trial 
(14.8 months and 30%, respectively) were significantly better than historical controls (11.2 
months and 13%, respectively). (Murphy et al. 2007) High-dose radiotherapy also improved 
the two-year local control from 38% (historical controls, Murphy et al. 2007) to 59%. 
Additionally, 12 of 50 patients (24%) receiving high-dose radiotherapy were able to undergo 
resection with good outcomes; 10 patients (83%) had R0 resection and five patients (42%) had 
a major pathological response. The median survival in these patients was 32 months. The trial 
also confirmed that elective lymph node irradiation is not required in this setting.  
 
Investigators at Washington University also reported a favorable progression-free and overall 
survival (13.9 and 23.1 months, respectively) for 25 patients with locally advanced disease and 
seven with borderline resectable disease following intensified radiation with 55 Gy in 25 
fractions. (Badiyan, 2014) These trials demonstrate that intensification of local therapy with the 
use of high dose radiochemotherapy and highly conformal techniques can be delivered safely 
and results in encouraging local control rates and OS.  
1.1.6 Respiration Motion and Gating
There is considerable respiratory-induced motion in the upper abdomen. This has been 
reported as a range of 2 mm to over 15 mm. (Minn 2009, Mori 2009, Song 2010, Goldstein 
2010, Feng 2009, Liang 2010) Methods to control for motion can include immobilization 
devices as well as respiratory gating. Four-dimensional computed tomography (4DCT) is used 
to measure this motion and to plan gated treatment. (Tai 2010; van Der Geld 2008) 
 
1.1.7 Image-guided Adaptive Radiation Therapy 
During RT, the location and shape of the pancreas vary significantly from day to day due to 
daily setup variations and physiological changes. (Liu 2010, Singh 2006, Wysocka 2010, 
Langen 2001) Singh et al. (2006) reported that, due to the large interfraction anatomical 
changes, the day-to-day V80% (volume covered by 80% isodose line) for the duodenum and 

 
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non-duodenal small bowel varied in the ranges of 30% to100% and one to 20%, 
respectively.(Singh 2006) Image-guided RT (IGRT) based on soft-tissue registration can 
address setup error and these inter-fractional shifts. (Tai 2010) Furthermore, online adaptive 
RT (ART) has the potential to fully account for the interfraction variations, including organ 
deformation. (Peng 2010, Feng 2011) With the respiratory motion eliminated/reduced by a 
respiration management technique, such as gating, the PTV margin can be reduced from 1–2 
cm to 0.3–0.5 cm by the use of IGRT and/or online ART. Because the PTV often overlaps with 
the duodenum and small bowel, such a drastic reduction in PTV margin would potentially 
reduce toxicities or allow RT doses to be escalated to eradicate the bulk of the tumor,  
(Bouchard 2009, Ogawa 2011, 2011a) and improve treatment outcome.  
1.1.8 Imaging in Pancreatic Cancer 
Pancreatic tumors are known to be hypoxic. (Kong IJROBP 2000) This may be due to 
hypoperfusion as these tumors have notoriously been resistant to antiangiogenesis agents. In 
fact, the dense fibrous stroma and relatively sparse vascularity of most pancreatic cancers 
may explain the resistance to treatment and is also the rationale for the imaging findings on 
contrast-enhanced MR and CT of pancreatic cancer. Normal pancreatic tissue typically 
demonstrates maximum enhancement in the early/arterial phase of contrast enhancement.  
 
The relative hypoperfusion/non-enhancement of the pancreatic tumor in comparison to the 
normal pancreas makes it most conspicuous during the early phase of contrast enhancement.  
In addition, it is more feasible to perform multiphasic post contrast evaluation of pancreatic 
tumor perfusion with MR than CT because there is no associated ionizing radiation concern 
with MR.  
 
The superior contrast resolution/ tissue differentiation of MRI typically makes it easier not only 
to detect pancreatic cancer but also to more accurately define the tumor volume in relation to 
the normal glandular tissue. (Gabata 1994, Semelka 1996) Not only is post contrast MR 
imaging superior to CT for defining the intra-glandular extent of pancreatic tumors, but there 
are other MR imaging sequences that are very helpful for distinguishing normal glandular 
tissue from tumor. The aqueous protein within the pancreatic acini is high signal on T1-
weighted imaging; subsequently, T1-weighted imaging can be used to differentiate tumor from 
normal parenchyma. (Semelka 2006). In addition, fluid sensitive T2-weighted sequences 
allow for very high-resolution imaging of the pancreatic duct and the ductal disruption 
associated with pancreatic adenocarcinoma. 

 
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In the past several years, diffusion-weighted imaging (DWI) has become much more common 
in abdominal MRI. Initial experience with DWI of the pancreas has been very encouraging. 
Early investigations have yielded very high sensitivity and specificity for the detection of 
pancreatic cancer. (Ichikawa  2007) In addition, DWI appears to be very promising in 
predicting early progression of disease in chemotherapy-treated patients.(Ueno 2009) This 
may offer much more insight into treatment response than available with CT. 
 
DWI is a very useful sequence for evaluating pancreatic cancer because it is very sensitive for 
detecting tissue that has relatively restricted diffusion in comparison with the adjacent normal 
tissue. (Semelka 1996) Pancreatic cancer has increased cellularity and a higher nucleus to 
cytoplasm ratio than normal pancreatic tumor. Therefore, the Brownian motion of water is 
significantly reduced compared to the adjacent normal pancreatic parenchyma. This results in 
higher signal in areas of the pancreas displaying restricted diffusion and DWI is subsequently 
quite sensitive for the detection of pancreatic cancer. (Ichikawa 2007) In addition, DWI 
appears to be quite promising for monitoring early treatment response/cell death prior to a 
change in tumor size. (Ueno 2009). Decreases in DWI signal can be correlated with treatment 
response/cell death prior to a reduction in tumor size and may be a more accurate way to 
assess response than simply a change in size as available with CT. Some of the seeming 
lack of response to treatment when using CT size criteria may in fact be a result of the 
shortcomings of CT in assessing response rather than the shortcoming of the treatment.   
 
Post contrast MR perfusion imaging may also provide some prognostic information regarding 
treatment response. (Akisik 2010) In a recently published study, higher perfusion values for 
the rate of transfer of gadolinium-based contrast to and from the extracellular space (Ktrans) in 
pancreatic tumors were correlated with better response to anti-angiogenic chemotherapy. 
Considering that tumor response to radiation therapy is dependent upon tissue oxygenation 
for the generation of the cytotoxic free radicals, measuring tumor perfusion may also yield 
important prognostic information prior to initiating radiation therapy. 
 
The pancreatic cancer protocol abdominal MRI with and without intravenous contrast will be 
utilized to stage, assist in treatment planning, and monitor treatment response for the patients 
enrolled in this study. The three MR sequences that will typically be utilized for contouring the 
radiation targets are T2 (duodenal wall delineation), fat-suppressed T1 (normal gland 

 
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delineation), and late arterial phase post-contrast, fat-suppressed T1 (tumor boundary and 
lymph node delineation; e.g., tumor appears dark, lymph nodes appear bright) because these 
sequences offer the best contrast resolution between tumor and normal pancreatic 
parenchyma. 
 
Abdominal MR scans will therefore be performed prior to radiation and following radiation to 
help to monitor response in addition to screening for extra-pancreatic disease. MR simulation 
will be used for the radiation planning in addition to CT simulation. The necessary MR imaging 
for radiation planning, as well as the use of MR to evaluate response, will be key to this study.  
 
PET imaging has also been explored in the staging of pancreatic tumors and is now an 
approved site for this test. PET imaging utilizes fluorodeoxyglucose (FDG), which is a glucose 
analog tagged with the fluorine 18 (18F) isotope. FDG is preferentially taken up by cells with 
high metabolic activity, such as pancreatic adenocarcinoma. Changes in PET activity may 
correlate and be a means to assess tumor response after radiation. There is already 
precedent for utilization of PET for early evaluation of treatment response in other 
malignancies, e.g., chemotherapy response in lymphoma. (Hoekstra 1993; Romer 1998; 
Jerusalem 2000; Mikhaeel 2000 ; Kostakoglu 2002) 
1.1.9 Considerations for Doses to Normal Structures  
Duodenal toxicity is of concern when treating unresectable pancreatic cancer and has often 
restricted radiation dose escalation strategies due to this intimately related organ. Similar 
challenges exist for the stomach and other portions of the small bowel.
The Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) review by 
Kavanagh et al. presents useful consensus guidelines on small bowel dose-volume effects for 
conventionally fractionated doses of the 45–50 Gy and suggest that the volume of the small 
bowel irradiated to 15 Gy, V15, should be less than 120 cc. (Kavanagh 2010) However, 
delivering a dose of 60–70 Gy in 2 Gy per fraction that will minimize surrounding normal tissue 
toxicity is challenging given the lack of dose-response data in this high-dose regimen. 
 
In a recent analysis, we performed modified linear quadratic (MLQ) (Guerrero and Li, 2004) 
based on iso-effective dose calculations using duodenum/small bowel dose-response data 
from reports whose fractionation schedules ranged from 1.5–25 Gy/fx (Prior 2014). Published 

 
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duodenum/small bowel dose-response data using a dose per fraction of 1.5–25 Gy were 
converted to MLQ equivalent dose in 2 Gy fractions (MLQED2) using parameters obtained by 
modified Lyman model fitting. Furthermore, a method of converting dose-response data at one 
level of NTCP to another NTCP level was also presented. Our findings indicate that these 
converted dose-response data from conventionally fractionated radiotherapy (CFRT) and 
stereotactic body radiation therapy (SBRT) reports were reasonably consistent with one 
another in the range of 55–65 Gy.  
 
There were three reports (Table 3) useful in determining duodenal planning constraints for the 
proposed dose escalation protocol. Two sets of iso-effective dose calculations are listed for 
each report: 1. Calculations of MLQED2 as presented in our analysis mentioned above; and 2. 
MLQ equivalent dose in 2.2 Gy per fraction (MLQED2.2) adjusted to an NTCP level of 15%. A 
brief summary of the reports useful in selecting planning constraints is given below. 
Murphy et al. (2010) 
A dosimetric model of NCI Common Terminology Criteria for Adverse Events (CTC) v3.0 
duodenal toxicity had been developed by Murphy et al. using SBRT dose-volume data from 73 
pancreatic cancer patients treated with CyberKnife. This study reported an association between 
12-month actuarial estimates of grade > 2 CTCAE duodenal toxicity (including ulceration, 
stricture, gastrointestinal (GI) hemorrhage, and perforation) and dose-volume parameters V20, 
V25, and the maximum dose to 1 cc of duodenum, D1 cc. According to MLQED2 calculations, 
this single fraction of 23 Gy is equivalent to 55.6 Gy delivered in 2 Gy fractions. Similarly, the 
other dose-volume constraints V20 and V25, are equivalent to V45.7 and V62.5. 
 
Verma et al. (2013)
The second report by Verma et al. reported on the duodenal toxicity of 112 women receiving 
IMRT to the para-aortic nodes for metastasis from various primary cancers (e.g., cervical, 
endometrial, ovarian, vaginal, vulvar, and others), receiving a dose of 45–66 Gy in 1.8–2.2 Gy 
per fraction. The authors found that the mean maximum dose of 63.3 Gy, dose to duodenum 
volume of 2cc, D2cc, of 61.2 Gy and a D5cc of 59.1 Gy was found in eight patients experiencing 
grade > 2 RTOG duodenal toxicity. Similar MLQED2 calculations on the data from Verma et al. 
suggest that the risk of grade > 2 duodenal toxicity could be limited to 7% if Dmax < 63.3 Gy, 
D2cc < 61.2 Gy, and D5cc < 59.1 Gy. 

 
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Huang et al. (2011)
A third report by Huang et al. reported dosimetric predictors of GI toxicity in a group of 46 
locally advanced pancreatic patients receiving 36 Gy in 2.4 Gy per fraction and concurrent 
gemcitabine. The authors report a 12 month GI toxicity rate of 8% provided the V25 < 45%. 
MLQED2 calculations found that V24.2 and V34 are equivalent to V25 and V35, respectively.
 
Dose-response SBRT data for the stomach and pyloric sphincter were found to be non-
existent, making it difficult to perform a similar MLQED2 analysis. Emami et al. (Emami 1991) 
state a TD50(1) (the dose corresponding to 50% complication probability for a uniformly 
irradiated whole organ) of 65 Gy, suggesting the stomach may be relatively more tolerant of 
higher doses than the duodenum. However, in light of the difficulty in performing a similar 
MLQED2 analysis, the duodenum dose-volume constraints will be used for the stomach. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 3. Description of studies included in the analysis of radiation induced duodenal toxicity. The 
MLQED2 and MLQED2.2 are the doses in 2 and 2.2 Gy fractions, respectively, delivered uniformly to 
the whole organ volume. (Prior 2014) 

 
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1.1.10 SMAD 4 expression
Smad4 (Dpc4) is a tumor suppressor gene that is inactivated in 53% of pancreatic cancer. It 
encodes a transcription factor that is involved in the regulation of expression of a broad set of 
genes; it has been implicated in the regulation of tumor microenvironment, and it has been 
correlated clinically with prognosis and the pattern of disease spread. (Crane 2011) Smad 4 
immunostaining of diagnostic cytology specimens  correlated with the pattern of disease 
progression in the series of Crane et al. Intact Smad4 expression had a local dominant 
pattern of disease progression and Smad4 loss had a distant dominant pattern of disease 
progression (p=0.016). (Crane 2011) The rapid autopsy series from Johns Hopkins University 
was the first to correlate Smad4 with the pattern of disease progression. (Iacobuzio-Donahue 
2009) Together, these studies contradict the perception that all patients with pancreatic 
cancer will die because of disseminated disease and emphasize that complications of local 
tumor progression are a significant source of disease-related mortality. Testing of Smad4 
expression prior to treatment (if tissue is available) may help to differentiate those patients in 
whom local therapy, in addition to systemic therapy, may alter their outcome and be a 
reasonable investment of their time and energy. 
 
2.0 
OBJECTIVES 
2.1 
Primary Objective 
To evaluate the efficacy of dose escalation to an MR-defined GTV of up to 69.75 Gy at 2.25 
Gy per fraction for unresectable pancreatic cancer and to determine two-year and median 
survival rates measured from the date of diagnosis and from the end of treatment. 
2.2
Secondary Objectives  
2.2.1 To evaluate local control based on imaging.  
2.2.2 To evaluate acute and late (> 3 months post treatment) radiation-induced toxicities for patients 
treated in this protocol.
2.2.3 To evaluate radiographic and biochemical response for patients treated with the proposed 
dose escalation using pre- and post-treatment MR and PET scanning in addition to routine 
surveillance CT scans and CEA/ CA 19-9 levels. 
2.2.4 To evaluate SMAD 4 expression vs patterns of relapse. 
3.0 
PATIENT SELECTION 
3.1 
Conditions for Patient Eligibility 

 
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3.1.1
Pathologically confirmed (histologic or cytologic), locally advanced, adenocarcinoma of the 
pancreas; patients must have unresectable disease based on institutional standardized 
criteria of unresectability or medical inoperability. Patients with bulky tumors (> 7cm on MRI), 
may not be eligible if the MR-defined SIB PTV volume is too large (> 400 cc). 
3.1.2 
Patients with and without regional adenopathy are eligible. 
3.1.3 
No convincing distant metastases, per PI discretion (for example, non-cancerous lung nodules, 
or equivocal lung or liver lesions that have been stable), based upon the following minimum 
diagnostic workup:  
3.1.3.1   History/physical examination, including collection of weight and vital signs, within 30 days prior 
to study entry; 
3.1.3.2  Diagnostic Abdominal/pelvic CT with IV contrast or Abdominopelvic MR scan with perfusion 
and diffusion-weighted sequences within 30 (+14) days prior to study entry.   If the initial 
screening abdominal/pelvic CT falls out of window and a PET scan is subsequently performed, 
the PET can be used as the 30 day screening scan to confirm no metastatic disease in place 
of repeating the CT.  The initial abdominal/pelvic CT would still serve as the comparator for 
subsequent abdominal/pelvic CT scans.   
3.1.3.3  Chest CT scan or X-ray within 30 (+14) days prior to study entry.  This is optional if PET scan 
including chest has already been performed at this time point.  
3.1.4 
Radiation treatment planning: abdominal MR with perfusion and diffusion-weighted sequences 
and abdominal CT. The abdominal MR will be done as a sim with interpretation. The CT sim 
will not be done with interpretation. PET scan is optional but encouraged (If PET is not allowed 
because of insurance or other issues, the patient is still eligible for the study). Ability to undergo 
abdominal MR scans for staging and radiation planning and follow up is mandatory. 
3.1.5 
Zubrod performance status 0-1 within 30 days of study entry.  
3.1.6 
 
3.1.7 
Heme Onc (Chem 24) and CA 19-9/CEA within 30 days prior to treatment, as follows:   
3.1.7.1 
000 cells/mm3;  
3.1.7.2
100,000 cells/mm3;  
3.1.7.3 
8.0 g/dl is acceptable.); 
3.1.7.4 Serum creatinine 
1.5 mg/dl; 
3.1.7.5 ALT or AST < 3 x upper limit of normal; 
3.1.7.6 Total bilirubin < 3.0 mg/dL; 
3.1.7.7 Alkaline phosphatase < 3 x upper limit of normal;

 
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3.1.7.8 Negative serum pregnancy test (if applicable).
3.1.8 
Ability to swallow oral medications. 
3.1.9
Patients must have had at least four months of prior systemic chemotherapy.
3.1.10   Patient must provide study-specific informed consent prior to study entry. 
3.1.11 Women of childbearing potential and male participants who are sexually active must practice 
adequate contraception.    
3.2 
  Conditions for Patient Ineligibility 
3.2.1 
Distant metastatic disease, second malignancy or peritoneal seeding. 
3.2.2 
Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a 
minimum of three years (For example, carcinoma in situ of the breast, oral cavity, or cervix 
are all permissible).
3.2.3 
Prior radiotherapy to the region of the study cancer that would result in overlap of       
radiation therapy fields.
3.2.4 
Any major surgery within 28 days prior to study entry (for example, insertion of a vascular 
access device, exploratory laparotomy and laparoscopy are not considered major surgery; 
biliary or gastric bypass is considered major surgery).
3.2.5 
Severe, active co-morbidity, defined as follows: 
3.2.5.1 Unstable angina and/or congestive heart failure requiring hospitalization within the last six 
months; 
3.2.5.2 Transmural myocardial infarction within three months prior to study entry; 
3.2.5.3 Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration; 
3.2.5.4 Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring 
hospitalization or precluding study therapy within 30 days before registration; 
3.2.5.5 Uncontrolled malabsorption syndrome significantly affecting gastrointestinal function; 
3.2.5.6 Any unresolved bowel or bile duct obstruction; 
3.2.5.7 Major resection of the stomach or small bowel that could affect the absorption of 
capecitabine; 
3.2.5.8 Acquired immune deficiency syndrome (AIDS) based upon current CDC definition; note, 
however, that HIV testing is not required for entry into this protocol. The need to exclude 
patients with AIDS from this protocol is necessary because patients receiving antiretroviral 
therapy may experience possible pharmacokinetic interactions with capecitabine. 
3.2.6 
Pregnancy or women of childbearing potential and men who are sexually active and not 
willing/able to use medically acceptable forms of contraception during the course of the study 
and for women, for three months after the last study drug administration and for men, for six 

 
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months after the last study drug administration; this exclusion is necessary because the 
treatment involved in this study may be significantly teratogenic.  
3.2.7
Women who are lactating at the time of registration and who plan to be lactating through 
three months after the last study drug administration. 
3.2.8 
Prior allergic reaction to capecitabine or gemcitabine. 
3.2.9 
Inability to undergo an MR of the abdomen/pelvis. 
3.2.10 Participation in another clinical treatment trial while on study.  
 
4.0 
REGISTRATION PROCEDURES 
The eligibility criteria must be completed, and an IRB-approved consent form must be signed 
before a participant can be registered and receive a study case number. The research 
coordinator at Froedtert & the Medical College of Wisconsin will assign case numbers in 
numerical sequence, 1–45.      
 
5.0 
RADIATION THERAPY 
Image-guided IMRT or three-dimensional conformal radiation therapy (3DCRT) with 
respiratory gating should be used. IMRT with simultaneously integrated boost is preferred 
due to the ability to decrease dose to the adjacent normal organs, including the stomach, 
duodenum, small and large bowels, kidneys, liver, and spinal cord. Rarely, insurance issues 
will prevent IMRT and then 3DCRT will be used (< 10% of patients). When 3D CRT is 
required, two 3DCRT plans, one for PTV50.4 and one for PTVboost, will be generated and 
delivered sequentially. 
Protocol radiation treatment must begin no sooner than 14 days or at physician discretion, after 
the last chemotherapy dose. A 3D and 4D CT and MRI must be obtained for treatment 
planning. A mid-treatment (weeks 2–5) replanning CT/MRI or MR sim may occur if necessary.
 
5.1
Localization, Simulation, and Immobilization 
Respiration correlated 3D and 4Dl CT, MRI and optional PET will be acquired and fused for 
target and OAR delineation.
Patients will be simulated (and treated) supine with arms up. Immobilization is required. An 
alpha cradle or body vac fix is necessary. 

 
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5.1.1
CT Simulation
Both intravenous and oral contrast must be used at the time of CT simulation acquisition,  
unless there is renal insufficiency or iodine allergy. CT slice thickness must be no greater 
than 3 mm. Approximately 10 ml of omnipaque will be mixed with 120 ml of water and True 
Orange drink mix for the CT simulation and two-thirds of this ingested approximately 30 
minutes prior to simulation. The remaining third will be given after formation of the alpha- 
cradle or vac-fix immediately prior to scanning.  
 
No abdominal compression can be used for gating. The CT at exhale (e.g., 50% phase) 
should be used for planning. The gating window should be selected such that the residual 
motion is less than 3 mm, for example, between 40% to 60% phases. The internal target 
volumes (ITV) should be obtained from the union of the target volumes delineated based on 
the selected-phase CTs, e.g., 40% and 60% phases. If there is very little motion between 
these phases, contouring on only the 50% phase is acceptable. All normal structures should 
be delineated based on the 50% phase CT. 
 
5.1.2  MR Simulation (Appendix V) 
Patients not undergoing dialysis will be receiving gadolinium-based contrast during MR 
simulation. A glomerular filtration rate (GFR) greater than 30 must be confirmed within 45 
days of the MR simulation for those patients identified with age greater than 60 years and/or 
history of hypertension, diabetes, or liver transplant. An IV should be placed in the antecubital 
vein for power injection of the contrast.   
 
Patients must be set up in treatment position on an MR-compatible flat tabletop couch insert 
and be immobilized using the devices created during CT simulation. Phased-array receiver 
coils should be utilized to facilitate use of parallel imaging. A 1-mg injection of glucagon 
should be administered IM to suppress bowel motion. Images should be acquired in the 
transverse plane, using navigator-gating, based on the liver-diaphragm interface, whenever 
possible. The imaging protocol must include T2-weighted images, diffusion-weighted images 
(DWI), fat-suppressed T1-weighted images, and fat-suppressed, late arterial phase, post-
contrast T1-weighted images. High order shimming over a reduced volume fully 
encompassing the patient is strongly recommended prior to any fat-suppressed T1-weighted 
imaging.   
 

 
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Upon completion of the MR simulation, and before transfer to a radiation treatment planning 
system, all images must be corrected for gradient nonlinearity-induced geometric distortion by 
applying a vendor-provided 3D distortion correction algorithm.
 
5.2 
 Target and Critical Structure Volumes for Treatment Planning
5.2.1 
Target Volume Definitions 
5.2.1.1 The ITV of the pancreatic head/body/tail and any suspicious lymph nodes is defined from the 
planning 4DCT. The GTV includes the primary tumor defined from the gated MRI (late arterial 
phase post contrast, T1 weighted and DWI and the optional PET, inside or adjacent to the 
pancreatic head or body or tail. The PTVboost is the GTV plus a 3–5 mm margin. The dose will 
vary depending on the normal tissue constraints as in Table 4. The adjacent luminal GTV 
should be excluded from the PTV boost. Use of a 3–5 mm PRV around the luminal GI 
structures can also be used to help exclude the adjacent GI structures from the boost PTV. 
This PTV will be labeled “PTV Eval.” 
5.2.1.2 The CTV Low dose is equal to the ITV (pancreatic head or body or tail including GTV), the adjacent 
vessels (SMA, celiac axis) and any suspicious lymph nodes.  
5.2.1.3 The PTVLow dose is defined as the CTVlow dose plus a uniform 5–10 mm expansion in all directions.  
5.2.2 
Critical Structures 
The normal structures to be contoured are: stomach, duodenum, small bowel, large bowel, 
left and right kidneys, liver, and spinal cord. Contour the kidneys, liver, stomach, and 
duodenum in their entirety (See Appendix VI for stomach/duodenal anatomy) and any other 
small bowel or large bowel that is within 2 cm of the PTVLow dose.
 
5.3
Dose Specifications and Dose Volume Constraints
The recommended treatment plan for this protocol is an IMRT plan due the ability to spare the 
adjacent normal organs Treatment planning will be done to achieve the highest dose 
plan (31 fractions) if the normal tissue dose constraints can be met. If the normal tissue 
dose constraints are not met, the dose will be adjusted down incrementally from 31 to 
30 to 29 to 28 fractions until those dose constraints are met. At least five fields are 
required. 3DCRT is only acceptable if there are insurance issues which occur in <10% of 
patients. Photon beams of at least 6 MV should be used.  
 
5.3.1 
Target Dose Specifications 

 
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The prescription dose to the PTVboost will be in 2.25 Gy daily fractions with number of fractions 
of 28, 29, 30, or 31, subject to the dose-volume constraints for the duodenum, stomach, 
colon, and small bowel. When possible, the prescription dose will cover 
90–95% of the 
PTVboost. This coverage can be lowered as needed to meet the luminal GI constraints. The 
PTV boost is defined by MR+/-CT.
 
A minimum dose equivalent of 50.4 Gy in 28 fractions will be prescribed to give 95 coverage 
of the PTVlow dose. The minimum dose within the PTVs must not fall below 95% of the 
prescribed dose. The PTV low dose will include the entire pancreatic head, body or tail, the 
MR-defined tumor, the associated blood vessels (SMA, celiac axis) and any suspicious 
lymph nodes.
 
Table 4: Target prescription doses
Target 
28 
fractions 
29 
fractions 
30 
fractions 
31 
fractions 
PTV50.4 
28           x 
1.80 Gy 
50.4 Gy 
29 
x 
1.75Gy 
50.75Gy
30           x 
1.70Gy 
51Gy
31 
x 
1.65Gy 
51.15Gy
PTVboost(SIB) 28           x 
2.25 Gy 
63 Gy 
29             x 
2.25Gy 
65.25Gy
30           x 
2.25Gy 
67.5Gy 
31 
x 
2.25Gy 
69.75Gy
*Note that the PTV boost dose (SIB) per fraction stays the same for all the dose levels but 
the PTV 50.4 dose per fraction varies. 
5.3.2 Normal Tissue Dose-Volume Constraints  
 
 
 
 
Structure
Constraints
Kidney
(L & R) 
Not more than 30% of the total volume can 
receive  18 Gy. If only one kidney is 
functional, not more than 10% of the volume 
can receive 
18 Gy.
duodenum, 
Stomach,
/small bowel 
and large bowel 
Max dose is the PTV boost dose(< 0.03 cc)
V56 < 5 cc (duodenum)
V45<30 cc (duodenum)
V45<75 cc (stomach)
V45< 135 cc (small bowel)
 
Liver
Mean dose < 28 Gy ; V30 < 30% 
Spinal cord
Max dose to a volume of at least 0.03 cc 
must be 
45 Gy 

 
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5.4
Treatment Delivery
5.4.1 Patient Positioning with IGRT 
Patient should be positioned as in the simulation. Respiration-gated kVCT(CT on rails) should 
be acquired at every fraction prior to the delivery of treatment and will be registered with the 
planning CT based on soft-tissue. If necessary, patient should be repositioned according to the 
shifts calculated from the registration (MV CT and KV cone beam CT are not allowed as they 
cannot be gated).  
5.4.2 Respiration Gated Delivery  
 
Treatment should be delivered with respiration gating using the gating window consistent with 
that used for the plan unless there is < 8 mm of superior/inferior motion measured on 4D CT. 
Real-time monitoring of patient respiration should be carried out during the delivery. Treatment 
should be interrupted if a significant change is observed in respiration.   
5.4.3 Online ART (optional) 
Patients should be treated with IGRT (Section 6.4.1). The pancreatic head (or body) should be 
delineated from the daily CTs for the first five fractions. Deformation of the pancreatic head or 
pancreas should be reviewed. If the deformation is found to be severe (i.e., the 5-mm margin 
expansion is not sufficient to cover the pancreatic head), the online ART process should be 
carried out on two days per week (e.g., Monday and Thursday) and at the last day of the 
treatment. On the other three days, the patient will undergo regular IGRT (Section 6.4.1). On 
the treatment days with the online ART, these steps will be followed: (1) set up the patient 
using laser maker alignment in the same way as for regular IGRT; (2) image the patient with 
the CT-on-rails in the same way as for regular IGRT, and transfer the images into the RealART 
system; (3) perform auto-segmentation with manual editing to obtain contours of the pancreatic 
head and duodenum; (4) replan based on the newly generated contours using the plan 
generated with the offline adaptive optimization (Section 6.4.4) or, for the first application of the 
online ART, using the original plan; (5) reconstruct the repositioning plan based on the new 
contours assuming the patient to be treated with the standard IGRT and compare with 
adaptive plan; (6) transfer the adaptive plan to the R & V system; (7) perform the independent 
monitor unit (MU) check and data transfer check using a quality assurance (QA) software tool; 
and (8) deliver the adaptive plan without the patient repositioning. Under rare situations, if the 
adaptive plan is not superior to the repositioning plan, the patient will be treated with standard 
regular IGRT.  

 
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5.4.4 
Offline Adaptive Optimization (Optional) 
Before each treatment with the online replanning (Section 6.4.3) to be performed, the offline 
adaptive optimization procedure should be performed following these steps: (1) reconstruct 
dose for each of the repositioning fractions after the previous online replanning fraction, using 
the CT of the day and taking into account the couch shifts; (2) register all daily CT images 
acquired at and after the previous online replanning fraction based on deformable registration; 
(3) accumulate dose delivered up to the latest fraction based on the deformable registration in 
previous step; (4) generate the desired plan (gold standard) by performing a full-scope 
optimization based on the CT of the latest fraction using the same dosimetric objectives as for 
the original plan; (5) calculate the residual imperfection by subtracting the accumulated dose 
from the desired dose; and (6) generate the adaptive optimization plan taking into account the 
residual imperfection. The adaptive plan will be used as the initial plan for the subsequent 
online replanning. 
 
5.5 
Documentation Requirements 
5.5.1 Quality Assurance Documentation Stored in the Department of Radiation Oncology via MIM and 
Mosaic  
The following documentation must be saved and available for review: 
The CT, MRI, PET images used for planning; 
The target and critical structure contours and the treatment plan; 
The results of patient specific IMRT QA;
The detailed patient setup and treatment delivery record; 
The daily treatment CTs and screen captures with daily shift data;
The online adaptive plans, if applicable; 
The patient respiration signals during the daily delivery;
The follow-up images (CT and MRI) and follow-up notes. 
5.5.2 Treatment Interruptions  
Treatment interruptions should be clearly documented in the patient’s treatment record. If the 
sum total exceeds 14 break days, the treatment will be considered deviation unacceptable.
5.6
Compliance Criteria  
5.6.1 Volume Definitions 
5.6.1.1 Variation acceptable 

 
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 Minimum dose within the PTV is less than 95% of the prescribed dose, but does not fall 
below 60% of this dose.
 Maximum dose within the PTV is greater than 110% of the prescribed dose, but does not 
exceed 115% of this dose. 
5.6.1.2 Deviation Unacceptable 
 Minimum dose within the PTV falls below 60% of the prescribed dose.
 Maximum dose goes above 115% of the prescribed dose. 
 Incomplete contouring of the entire GTV or PTV. 
 Use of different margins than specified in Section 5.2 for the CTV and PTV. 
 Over contouring of the GTV by > 30 cc.  
 
5.6.1.3 Elapsed Days 
 Per Protocol – No break days. 
Variation Acceptable – Up to nine break days. 
 Deviation Unacceptable – More than 14 break days. 
 
Evaluation 
Total 
Dose 
Elapsed 
Days 
Per Protocol
 
38-45 
Variation 
Acceptable 
 
 
47-54 
Deviation 
Unacceptable 
>10% 
 
> 55 
 
5.6.2
Compliance Criteria for Critical Structures 
The compliance criteria for the critical structures identified for this protocol are based on the 
planning constraints presented in Section 5.3. 
5.6.2.1 Kidneys: 
Per protocol: the requirements in Section 5.3.2 are fulfilled. 
Variation Acceptable: If two kidneys are functional, >20% but < 30% of total kidney volume 
receives 
 
 

 
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 Deviation Unacceptable: If two kidneys are functional,  30% of total kidney volume 
receives 
18 Gy. If one kidney is functional, 
20% of total kidney volume receives 
Gy.  
5.6.2.2 Spinal cord: 
Per protocol: the requirements in Section 5.3 are fulfilled.
 Variation Acceptable : None. 
 Deviation Unacceptable: Max dose > 45 Gy to a volume that is at least 0.03 cc.   
5.6.2.3 Liver:  
 Per protocol: the requirements in Section 5.3 are fulfilled. 
 Variation Acceptable: None. 
Deviation Unacceptable : The mean liver dose exceeds 28 Gy. 
 
5.7 
Radiation Therapy QA and Reviews 
After the first 10 patients are treated at Froedtert & the Medical College of Wisconsin, 
consideration will be given to opening the study up to other select institutions. Institutions 
interested in participating in this protocol should submit the following document for review by 
the physics study chair: 
(1) Description of MR simulation (scanner details, sequences, positioning, coils).
(2) Description of IMRT planning, QA and delivery process and technology. 
(3) Description of IGRT process and technology. 
(4) Description of motion management method.  
 
The necessary technologies required in this protocol include: 4DCT, MRI, IMRT, respiration 
gating or equivalent motion management technology, soft-tissue based patient positioning 
using diagnostic-quality CT.  
 
The first case enrolled by each radiation oncology facility will undergo a rapid review by Drs. 
Erickson and Li. In this process, the treatment plan is submitted immediately (within 24 hours) 
after it is finalized. The case may proceed to treatment following planning without waiting for 
review and approval. The case will be reviewed in a timely manner with feedback given to the 
submitting radiation oncology facility. Corrections and resubmission of data will be requested 
for cases that do not meet contouring, dose-volume and quality assurance criteria.  

 
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All cases enrolled on trial will be reviewed. Corrections and resubmission of data will be 
requested for cases that do not meet contouring, dose-volume and quality assurance criteria.  
5.8 
Radiation Therapy Adverse Events  
5.8.1
Adverse Event (AE) 
Radiation therapy would stop early if the patient has significant grade 3 toxicities.  
  
Toxicity
Parameters 
Agent
Modification 
Hematologic 
grade 3 platelets
 
RT 
Dose 
modification per 
investigator 
discretion.
Clinically significant 
treatment-related 
nonhematologic toxicity 
 
RT 
Dose 
modification per 
investigator 
discretion.
GI 
Grade 3 Intractable 
abdominal pain, nausea, 
vomiting, gastritis, gastric 
ulcer, duodenal ulcer, 
duodenitis; dyspepsia, 
colitis
over baseline or IVF > 24 
hr. Hospitalization needed. 
RT 
Dose 
modification per 
investigator 
discretion. 
5.9
Radiation Therapy Adverse Event Reporting  
See Section 6.4 for adverse event reporting.
6.0
DRUG THERAPY
Institutional participation in chemotherapy studies must be in accordance with the Medical 
Oncology Quality Control guidelines. 
Protocol drug treatment must begin within 30 days from study entry. The screening weight is 
used to calculate the BSA unless changed by > 10%. 
 
6.1 
Treatment 
Patients will receive either gemcitabine or capecitabine at the discretion of the medical    
oncologists. Gemcitabine will be given once per week on Monday, Tuesday or Wednesday  
and capecitabine will be given orally twice per day. Drug dose adjustments can occur at the 
start of treatment at the discretion of the treating oncologist using guidelines in Section 7.5.1.1 
.  

 
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6.1.1 Gemcitabine 400 mg 1m2 IV weekly x six doses. Administer over 30 to 40 minutes
6.1.2 Capecitabine 825 mg/m2 po bid. Monday – Friday on days of radiation use 500 mg tablets, 
round to the nearest 500 mg dose. If there is an uneven number of pills, give the extra dose 
with the evening administration (e.g., three in AM and four in PM). Take 30 to 60 minutes after 
eating. For patients with GFR 30 – 50: 75% dose, GFR <30: hold drug (per up to date).
 6.2 
Gemcitabine (HCl) Agent Information 
See package insert for comprehensive information.
6.2.1 Formulation 
Gemcitabine is an antineoplastic agent that is structurally related to cytarabine. It is a 
pyrimidine analogue that is cell-cycle specific. Gemcitabine is available commercially as a 
lyophilized powder in sterile vials containing 200 mg or 1 gram of gemcitabine as the 
hydrochloric salt (expressed as the free base) formulated with mannitol and sodium acetate.
6.2.2 Mechanism of Action
Gemcitabine is cytotoxic to cells undergoing DNA synthesis (S-phase) and also blocks the 
progression of cells through the G1/S- phase boundary. Gemcitabine is converted 
intracellularly to gemcitabine-5'-triphosphate, its active form. Steady-state plasma levels of 
gemcitabine occur within 15 minutes after starting the infusion. The elimination half-life of 
gemcitabine ranges from 32 to 638 minutes, depending on the age and gender of the patient 
and the rate of administration of gemcitabine. 
6.2.3 Preparation 
Drug vials will be reconstituted with normal saline added to the vial to make a solution ideally 
containing 10 mg/mL. The concentration for 200-mg and 1-g vials should be no greater than 40 
mg/mL. 
6.2.4 Administration 
An appropriate amount of drug will be prepared with normal saline and administered as a 30- 
to 40-minute intravenous infusion. 
6.2.5 Adverse Events 
The major side effects observed with gemcitabine include leukopenia, thrombocytopenia, 
anemia, and a collection of signs and symptoms referred to collectively as a flu-like syndrome 
with fever, headache, rigors, nausea, diarrhea, itchy skin rash, myalgia, and anorexia. Other 
side effects have included fatigue, peripheral edema, and proteinuria. Less likely side effects 
include abnormal renal and liver function tests, vomiting, constipation, malaise, and anorexia. 
Rare side effects include Stevens-Johnson syndrome (severe skin reaction) and shortness of 
breath, cough, inflammation or scarring of the lung. Rare side effects have included hemolytic 

 
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uremic syndrome/renal failure and liver failure, which have occurred following therapeutic 
gemcitabine therapy. Cardiac dysfunction (myocardial infarction, congestive heart failure, and 
atrial fibrillation) have been infrequently reported.
6.2.6 Storage and Stability 
The lyophilized product should be stored at controlled room temperature (20–25°C or 68–79° 
F). Once the drug has been reconstituted, it should be stored at controlled room temperature 
and used within 24 hours. The manufacturer recommends solutions of gemcitabine not be 
refrigerated as crystallization may occur. 
6.2.7 
Supply 
Gemcitabine is commercially available. 
6.3 
Capecitabine Agent Information
See package insert for comprehensive information. 
6.3.1 
Formulation 
Capecitabine is supplied as a biconvex, oblong film-coated tablet for oral administration. 
Approximately 500 mg tablets will be utilized in this study. Dosages will be rounded to the 
nearest 500 mg.  
6.3.2
Mechanism of Action
Capecitabine is an oral prodrug of 5-fluorouracil. Metabolized in the liver to 5'-deoxy-
fluorocytidine, subsequently converted to 5'-deoxy-5-fluorouridine which is then hydrolyzed to 
5-fluorouracil (active). Peak plasma levels occur in 90 minutes, and elimination half-life is 45 
minutes. 
6.3.3 
Preparation 
This is an oral agent. Food delays the time to peak plasma level by about 90 minutes, and 
reduces the peak plasma concentration about 60%. Despite the effects of food on 
capecitabine pharmacokinetics, the manufacturer recommends giving the drug at the end of a 
meal because established safety and efficacy data are based on administration with food. 
6.3.4 
Administration 
The capecitabine daily dose is given orally in two divided doses (approximately 12 hours 
apart) at the end of a meal. Dosages will be based on the dosing guidelines in 7.1.2; the
tablets should be taken with water. 
6.3.5 
Potential Drug Interactions 
6.3.5.1 Antacids
The administration of 20 mL of an antacid containing aluminum hydroxide and magnesium 
hydroxide may result in an increase in the area under the concentration-time curve (AUC) and 

 
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maximum concentration (Cmax) of capecitabine of 16% and 35%, respectively. These changes 
were not considered clinically significant. 
6.3.5.2 Oral Anticoagulants
Altered coagulation parameters and/or bleeding, including death, have been reported in 
patients receiving capecitabine and coumarin-derivative anticoagulants. Post-marketing 
reports have revealed clinically significant increases in prothrombin time (PT) and INR in 
patients who were stabilized on anticoagulants when capecitabine was initiated. These events 
occurred within several days to several months after concurrent therapy was initiated. 
Patients receiving capecitabine and an oral anticoagulant should be closely and regularly 
monitored. 
6.3.5.3 Phenytoin 
Some patients receiving capecitabine and phenytoin may experience phenytoin toxicity as a 
result of increased phenytoin plasma levels. Phenytoin levels should be closely monitored in 
patients taking concomitant phenytoin and capecitabine. The dose of phenytoin may need to 
be reduced. 
6.4 
Adverse Events 
Only toxicities related to treatment require dose modifications. For patients experiencing
adverse events unrelated to treatment (such as deep venous thrombosis, pulmonary embolus 
or non-neutropenic infection), when treatment is resumed after recovery from these adverse 
events, no dose modifications are required. 
Common side effects from capecitabine include diarrhea (which may be severe), dermatologic 
effects (hand-and-foot syndrome referred to as palmar-plantar erythrodysesthesia), 
hematologic effects (neutropenia, thrombocytopenia, anemia, and lymphopenia), weight gain, 
and gastrointestinal effects (diarrhea, nausea, vomiting stomatitis, abdominal pain, and 
constipation). Uncommon side effects include hepatotoxicity (hyperbilirubinemia). Rare side 
effects may include cardiovascular effects (myocardial infarction, dysrhythmias, and 
cardiomyopathy). 
6.4.1
Storage and Stability
Tablets should be stored at controlled room temperature (25°C) in tightly closed containers 
with excursions to 15–30°C permitted.
6.4.2 
Supply 
Capecitabine is commercially available.
6.5 
Dose Modifications 

 
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Dose modifications will be made according to the greatest degree of toxicity. Adverse events 
will be graded according to Common Terminology Criteria for Adverse Events (CTCAE) (per 
Section 7.7). 
Use NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 for 
assessment of toxicity. 
 If multiple toxicities are seen, the dose reduction should be based on the most severe 
toxicity experienced. 
 Dose reduction is not permanent and may be adjusted week to week at treating 
physician’s discretion.
If chemotherapy is held due to a grade 2 toxicity, radiation therapy should continue.
If the patient develops a non-hematologic grade 3 toxicity related to chemotherapy, the 
chemotherapy must be held until the toxicity has resolved to grade 1. If the toxicity has not 
resolved after two weeks, protocol therapy should be discontinued, and the patient treated at 
the discretion of the investigator.  
 
6.5.1 
Hematologic Toxicity  
Dose modifications according to blood counts the day of treatment are at the investigator’s 
discretion using the following as a guideline. The investigator may make adjustments per their 
discretion for patient safety purposes or other circumstances (e.g., anticoagulation or on 
Plavix®, history of infection, etc.).  
Gemcitabine Dose Modifications 
ANC > 1,000 and platelets >100,000 100% 
ANC 750–999 or platelets 75,000–99,000 75% 
ANC 500–749 or platelets 50,000–74,000 50% 
ANC < 500 or platelets < 50,000 hold  
Capecitabine Dose Modifications 
ANC > 1000 and platelets > 100,000 100% 
ANC 750–999 or platelets 75,000–
Reduce by 500 mg per day 
ANC 500–749 or platelets 50,000–74,000 Reduce by 1000 mg per day 
ANC < 500 or platelets < 50,000 hold until recovery   
 
6.5.2 
Non-hematologic Toxicity 

 
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Patients with adverse events not related to treatment, such as cholangitis from blocked biliary 
stents or pulmonary embolus from hypercoagulable state, after recovery from these adverse 
events, on resumption of treatment, do not require dose reductions when treatment is 
resumed. 
6.6
Adverse Events 
This study will utilize the descriptions and grading scales found in the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 for grading all adverse events.  
 
6.6.1 
Adverse Events (AEs) 
Adverse events and serious adverse events will be submitted to the MCW IRB following their 
reporting criteria. Please refer to the DSMB Section 10.3.2 for the AE/SAEs that will be 
collected and reported for this protocol.
 
Adverse Event: For data collection and analysis, all unexpected grade 3, and all grade 4 and 
5 adverse events will be captured for up to two years post treatment, death, or initiation of a 
new therapy, whichever occurs first. 
 
Serious adverse event: For data collection and analysis, serious adverse events will be 
captured from first treatment date for up to 30 days post treatment, death, or initiation of a 
new therapy, whichever occurs first. 
 
7.0
OTHER THERAPY 
7.1
Permitted Supportive Therapy
All supportive therapy for optimal medical care will be given during the study period at the 
discretion of the attending physician(s) within the parameters of the protocol and documented 
on each site’s source documents as concomitant medication 
Patients should receive full supportive care, including transfusions of blood and blood 
products, antibiotics, antiemetics, etc., when appropriate. The reason(s) for treatment, 
dosage, and the dates of treatment should be recorded in the institution’s source 
documentation.  
7.1.1 
Prophylaxis for Gastric Ulceration during Chemoradiation  

 
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It is recommended that patients be on a proton pump inhibitor during and for one month after 
radiation. If any new epigastric pain develops, ulceration should be expected and Gaviscon® 
liquid should be started. Upper endoscopy may be performed as clinically directed. 
7.1.2 
Anticoagulants: Caution Concerning Co-administration of Warfarin and Capecitabine 
A significant interaction occurs with co-administration of capecitabine and warfarin that can 
result in severe prolongation of the prothrombin time and resultant increased risk of severe 
bleeding. Patients requiring warfarin should have their prothrombin time monitored carefully 
according to institutional guidelines. Low molecular weight heparin does not interact with 
warfarin or capecitabine and is the preferred agent for patients requiring anticoagulation.
7.1.3 
Hematopoietic Growth Factors 
7.1.3.1 Erythropoietin is allowed. 
7.1.3.2 Myeloid growth factors may be utilized to treat CTCAE grade 3–4 ANC. 
7.2
Non-Permitted Supportive Therapy 
7.2.1 
Other investigational chemotherapeutic agents. 
7.2.2 
Other chemotherapeutic agents.
7.2.3 
Other monoclonal antibody. 
7.2.4
Sorivudine or brivudine A.
7.2.5 
Cimetidine. 
 
8.0
PATIENT ASSESSMENTS 
8.1
Study Parameters: See Appendix II. 
8.2
Evaluation During Treatment  
8.2.1 
In all clinic visits and weekly during each cycle, sites will question patients regarding 
compliance with study instructions.
8.3
Measurement of Response  
Response will be evaluated in this study using the international criteria proposed in the 
Revised Response Evaluation Criteria in Solid Tumors (RECIST) Guideline version 1.1 (Eur J 
Cancer. 2009;45:228–247.)  
See https://ctep.cancer.gov/protocoldevelopment/. CA  19-9 and CEA levels will also be 
followed. 
Abdominal CT imaging with IV contrast using 5-mm maximum slice thickness is 
recommended for evaluation of the primary tumor. CT will be obtained within 30 days prior to 
starting radiation and will be obtained 30 days post treatment to assess for response to 

 
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treatment as well as resectability. Abdominal MR is required prior to radiation for radiation 
planning and at three months following completion of the radiation. Additional MR scans every 
six months for the first two years should be obtained and alternated with CT scans every six
months. This will result in a diagnostic scan every three months. After two years, alternating 
abdominal MR and abdominal CT scans will be obtained every 12 months until year 5. This 
will result in a diagnostic scan every six months. After year 5, a CT abdomen scan will be 
obtained annually. Changes in perfusion (Ktrans) and diffusion (ADC) with respect to the 
pretreatment MR will be documented in addition to changes in tumor size.  
A PET scan should be performed three months post treatment and on an as-needed basis 
thereafter. (PET scan is optional but encouraged; if the patient cannot tolerate it or if it is not 
approved by insurance, the patient can still participate in the study.) 
o Measurable disease: Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as  20 mm by 
chest X-ray, as 10 mm with CT scan, or 10 mm with calipers by clinical exam. All 
tumor measurements must be recorded in millimeters (or decimal fractions of 
centimeters). 
o Non-measurable disease: All other lesions (or sites of disease), including small lesions 
are considered non-measurable disease. Lesions considered truly non-measurable 
include: leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitic 
involvement of skin or lung, inflammatory breast disease, and abdominal 
masses/abdominal organomegaly identified by physical exam that is not measurable by 
reproducible imaging techniques  
 
Response Criteria: Evaluation of Target Lesions 
 
Complete 
Response 
(CR): 
Disappearance of all target lesions; Any pathological 
lymph nodes (whether target or non-target) must have 
reduction in short axis to <10 mm. 
Partial Response (PR): At least a 30% decrease in the sum of the diameters 
of target lesions, taking as reference the baseline 
sum diameters. 

 
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Progressive 
Disease 
(PD): 
At least a 20% increase in the sum of diameters of 
target lesions, taking as reference the smallest sum 
on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase 
of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm. (Note:  the appearance of 
one or more new lesions is also considered 
progressions). 
Stable Disease (SD):
Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as 
reference the smallest sum diameters while on study.
8.4
Criteria for Discontinuation of Protocol Treatment
Protocol treatment may be discontinued for any of the following reasons:
 Progression of disease. 
 Adverse events, as described in Sections 6.8.1 and 7.5. 
Delays in protocol treatment greater than four weeks. 
 
 
If protocol treatment is discontinued, follow-up and data collection will continue as 
specified in the protocol.  
8.5
Summary of Dosimetry Digital Data (will only be needed if protocol open to other 
institutions with an amendment) 
Item 
Preliminary Dosimetry Information (DD)
Digital Data:   
 CT and MR data, critical normal structures, all GTV, CTV, 
and PTV contours.  
 Digital beam geometry for initial and boost beam sets. 
 Doses for initial and boost sets of concurrently treated 
beams. 

 
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 Digital DVH data for all required critical normal structures, 
GTV, CTV, and PTVs for total dose plan (DV).
9.0   
TISSUE/SPECIMEN ANALYSIS 
SMAD 4 TISSUE ANAYSIS 
 
SMAD 4 testing will be done on specimens from prior biopsy tissue pretreatment if possible. 
SMAD 4 immunostaining should be performed on the biopsy specimens if possible from the 
original biopsy material, or any biopsy material. Testing will be done at the Medical College of 
Wisconsin laboratories. SMAD 4 test results will be included in the patient’s research chart.
SMAD 4 testing can be repeated post treatment if the patient is undergoing surgery.
The PI will contact the clinical research coordinator (CRC) with a list of subjects for SMAD 4 
testing. The CRC will notify the CTO lab staff to request tissue and deliver tissue to the 
Genomic Science Precision Medicine Center. One to two blocks of tissue will be requested 
for SMAD 4 analysis. 
 
10.0 STATISTICAL CONSIDERATIONS  
10.1 Study Endpoints 
10.1.1 Primary Endpoint  
Two-year survival probability and median survival time starting diagnosis. 
10.1.2 Secondary Endpoints 
Local control as defined by imaging.
Acute and late (> 3 months post-treatment) toxicities (CT CAE). 
Adverse events at any time.
Imaging/Marker Response (MR/CT +/- PET; CA 19-9/CEA).  
SMAD 4 Expression vs. patterns of relapse.
 
10.2 Sample Size  
The historical value of median survival time, taken as the average value from reported studies 
for unresectable pancreatic cancer treated with radiation and chemotherapy, is approximately 
15 months starting from the end of treatment. Assuming survival time has an exponential 
distribution, this value leads to two-year survival probability of around 33%. We assumed that 
more patients will be eligible for the study when this protocol opens. We plan to accrue 23 
patients in three years, accruing seven, eight and eight patients for first, second and third 
years, respectively. The study will be closed at end of the fourth year. We expect the median 

 
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survival time will be double to around 30 months and lead to a two-year survival probability of 
around 59%. Based on exponential distribution and on a one-sided test with a significance 
level of 5%, we will have 80% power to detect at least a 15-month increase in median survival 
time. Allowing 5% subjects to withdraw, we plan to accrue 23 patients, accruing seven, eight 
and eight patients in the first, second and third years, in the final study. 
 
Analysis Plan 
Kaplan-Meier method will be used to estimate the two-year survival probability and median 
survival time with 95% confidence interval. Fitting an exponential distribution and one-side test 
for the null hypothesis of median = 15 month versus alternative of median > 15 month will be 
tested.
Descriptive statistics and survival analysis methods will be used to analyze the secondary 
endpoints presented in Section 11.1.2.  
 
10.2.1 Evaluation of Adverse Events for MTD 
Adverse events will be scored according to the NCI CTCAE version 4 criteria. Dose-limiting 
toxicity (DLT) is defined as any of the following occurring during chemoradiation or within 21 
days from the completion of chemoradiation and being reported as definitely related to 
treatment:
 Grade 4 non-hematologic toxicity except grade 4 hyperglycemia unless associated with 
acidosis (pH < 7.3), hyperosmolar state (serum osmolality > 310 mOsm/kg), or ICU 
hospitalization. 
 Grade 4 thrombocytopenia or neutropenia toxicity lasting > 7 days. 
 Grade 3 toxicity due to chemoradiation, preventing treatment for > 7 days or causing 
bleeding, ulceration, perforation, fistula formation or obstruction of the duodenum, 
stomach or small or large bowel and the study re-evaluated for reconsideration of dose 
to the PTV boost and to these organs at risk. 
 Elevation of ALT or AST > 10 x upper limit of normal for > 7 days (and not due to 
blocked stent or disease progression) also will be considered a DLT. 
 Any grade 5 AE.  
 We will evaluate and monitor grade 4 and 5 GI toxicity after the first 10, 15, and 20 
patients enrolled the study. A 10% incidence of grade 4 and 5 GI toxicity occurring in 
the enrolled patients will trigger stopping enrollment so that the protocol can be 

 
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reviewed. A Pocock-type boundary with the lower limit of 95% confidence interval will be 
used for monitoring toxicity. At planned interim monitoring points, if no more than four, 
five, or six GI toxicities occur, the study will continue to its full enrollment of 23.
10.2.2
Dose Escalation 
Dose escalation will be based on meeting the recommended dose constraints for the normal 
tissues. The highest dose will be attempted first and the PTV 50.4 and PTV boost doses will 
be decreased until the normal tissue constraints can be met. Treatment planning will be done 
to achieve the highest dose plan (31 fractions) if the normal tissue dose constraints can be 
met. If the normal tissue dose constraints are not met, the dose will be adjusted down 
incrementally from 31 to 30 to 29 to 28 fractions until those dose constraints are met.  
10.2.3 Patient Accrual  
Patient accrual is projected to be 23 patients in three years, accruing seven, eight and eight 
patients for the first, second and third years, respectively.  
 
10.3
Analysis Plan 
10.3.1 Interim Reporting 
Interim reports with statistical analyses are prepared every six months and reported to the IRB 
annually until the primary endpoint results have been presented. In general, the interim 
reports will contain information about: 
 The patient accrual rate with projected completion date, 
 Institutional accrual, 
 Pretreatment characteristics, 
Compliance rates of treatment delivery with respect to the protocol prescription,
The frequency and severity of adverse events due to protocol therapy. A safety review will 
be done after completing treatment of the first three patients.
The protocol will report any grade 3 duodenal small or large bowel or stomach 
toxicities to include bleeding, ulceration, perforation, fistula formation, or 
obstruction of the stomach, duodenum, small or large bowel. 
 The protocol will be temporarily closed to accrual for any unexpected non-hematologic grade 
4 or 5 toxicities and the study will be re-evaluated.
10.3.2 Data Safety Monitoring Board (DSMB) Review  

 
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To monitor the safety of this study, the Medical College of Wisconsin Cancer Center Data Safety 
Monitoring Committee (MCW CC DSMC) Cancer Center will review this study twice per year or 
for every five patients entered until all participants have completed treatment.
 
A summary of the MCW CC DSMC activities are as follows: 
Review the clinical trial for data integrity and safety.
Review all unexpected grade 3, and all grade 4, and 5 adverse events, as well as any 
others requiring expedited reporting as defined in this protocol. (Grades 4 and 5 events 
must be reported to the DSMC within five calendar days of study staff’s knowledge.)  
 Review all DSM reports. 
 Submit a summary of any recommendations related to study conduct. 
 Terminate the study if deemed unsafe for patients. 
 
A copy of the MCW CC Data and Safety Monitoring Plan and membership roster will be 
maintained in the study research file and updated as membership changes. The committee 
will review reports from the study PI twice annually (or more frequently if needed) and provide 
recommendations on trial continuation, suspension or termination as necessary. Any available 
DSMC letters will be submitted to the IRB of record as required. 
 
10.3.3  Analysis for Reporting the Initial Treatment Results 
10.3.3.1 Local control/ Treatment response 
RECIST criteria for MR and CT and biochemical marker response  
Local control - if local progression was not first progression, local progression will be 
determined by two consecutive imaging reports showing primary tumor growth and 
confirmed as progression by investigator; median survival and 1 year overall survival 
Acute and late toxicity assessment 
SMAD4 vs. Pattern of relapse 
10.3.3.2 Efficacy Endpoints 
This analysis will be limited to the patients who completed treatment when these patients 
have potentially been followed for one year. Overall survival will be estimated with the 
Kaplan-Meier method (Kaplan 1958). 
 
 
 

 
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Appendix I NCCN Criteria 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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APPENDIX II STUDY PARAMETER TABLE  
Trial Period: 
Screening 
On Treatment 
Follow-Up 
Scheduling Window: 
Within 30 days prior 
to concurrent 
treatment 
Assessed every 5 radiation 
treatments or at 
investigator discretion 
30 
days 
(+/- 7 
days)
Every 3 months 
until 2 years (+/- 
1 month) 
Every 6 months’ 
years 2-5 (+/- 1 
month) 
Annually after 
year 5 (+/- 1 
month) 
PHYSICAL
 
History
X
X
X
X
X
X
Physical with Weight and 
Vital Signs
X 
X 
X 
X 
X 
X
Response Assessment
X
X
X 
X
X
Performance Status
X
X
X 
X 
X
PATHOLOGY 
 
Pathologically Confirmed 
Disease 
X  
(prior to study 
entry)
 
 
 
LABORATORY 
 
CBC w/ diff; platelets, ANC
X 
X 
X7 
X7
X7
X7 
Creatinine, ALT or AST, Total 
Bilirubin, Alkaline Phosphate 
X 
X 
X7 
X7 
X7 
X7 
NA, K, CI, Mg, CO  
X 
X 
X7 
X7
X7
X7 
CA19-9 & CEA 
X 
 
 
 
Serum Pregnancy Test (if 
applicable) 
X 
(Before radiation 
simulation) 
 
 
 
IMAGING 
 
CT Abdomen & Pelvis (within 
30 (+ 14) days for screening 
scan)²
X 
 
X 
X¹ 
(Months: 6, 12, 
18, 24) 
X¹ 
(Months: 36, 48, 
60) 
X¹ 
MR Abdomen 
X 
 
 
X¹  
(Months: 3, 9, 
15, 21) 
X¹ 
(Months: 30, 42, 
54) 
PET Scan (Not Mandatory)² 
X 
 
 
X 
 
Chest CT or CXR  (within 30 (+ 
14) days for screening  scan)² 
X5
 
  
 
 
CT sim Abdomen and/or MR 
sim Abdomen for Radiation 
Planning 
X  
X 6 
(weeks 2-5 if 
necessary) 
 
OTHER
 
Adverse Event Evaluation 
(And as needed based on 
reporting requirements)
 
X 
X 
X 
 
 
Tissue for SMAD 4 Testing4 
 
X 
X 
 
1.Follow-up Imaging: CT Chest or CXR to be completed until disease progression. MR Abdomen and CT Abdomen and Pelvis are to be completed until disease 
progression. After disease progression, if CT Abdomen and Pelvis or MR Abdomen are still obtained as part of SOC, data will continue to be collected as available but 
is not required.
2.PET Scan: Not mandatory but suggested one month prior and 3 months’ post. If the initial screening abdominal/pelvic CT falls out of window and a PET scan is 
subsequently performed, the PET can be used as the 30-day screening scan to confirm no metastatic disease in place of repeating the CT. Screening chest CT or CXR is 
optional if PET scan including chest has already been performed at this time point. 
3.Follow-up Chest CT or CXR: Alternated every 3 months, however a CT is preferred. After year 5 the Chest CT or CXR is to be completed annually with the CT 
abdomen and pelvis.   
4.SMAD 4 Testing: If possible- Pre-treatment and Post-treatment specimens obtained  (if post-treatment surgery performed) 
5.Optional if:  PET scan including chest was already performed for this timepoint 
6.CT/MRI  SIM or MR SIM  abdomen as clinical indicated, per MD discretion 
7. Laboratory tests will be performed at the investigator discretion
 
 

 
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APPENDIX III 
 
ZUBROD PERFORMANCE SCALE 
 
0 
Fully active, able to carry on all predisease activities without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry 
work of a light or sedentary nature. For example, light housework, office 
work  
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours  
3 
Capable of only limited self-care, confined to bed or chair 50% or more of 
waking hours 
4 
Completely disabled. Cannot carry on self-care. Totally confined to bed 
5 
Death  
 

 
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APPENDIX IV 
 
AJCC STAGING SYSTEM 
Edge, SB, ed. AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2010.
EXOCRINE AND ENDOCRINE PANCREAS 
Primary Tumor (T) 
TX 
Primary tumor cannot be assessed 
T0 
No evidence of primary tumor 
Tis 
Carcinoma in situ* 
T1 
Tumor limited to the pancreas, 2 cm or less in greatest dimension 
T2 
Tumor limited to the pancreas, more than 2 cm in greatest dimension 
T3 
Tumor extends beyond the pancreas but without involvement of the celiac axis or the superior 
mesenteric artery 
T4 
Tumor involves the celiac axis or the superior mesenteric artery (unresectable primary tumor) 
*This also includes the “PanInIII” classification. 
 
 
Regional Lymph Nodes (N) 
 
NX 
Regional lymph nodes cannot be assessed 
N0 
No regional lymph node metastasis 
N1 
Regional lymph node metastasis 
 
 
Distant Metastasis (M) 
 
M0 
No distant metastasis 
M1 
Distant metastasis 
*This also includes the “PanInIII” classification 
 
Stage Grouping 
 
Stage 0 
Tis 
N0 
M0 
Stage IA 
T1 
N0 
M0 
Stage IB 
T2 
N0 
M0 
Stage IIA 
T3 
N0 
M0 
Stage IIB 
T1 
N1 
M0 
 
T2 
N1 
M0 
 
T3 
N1 
M0 
Stage III 
T4 
Any N 
M0 
Stage IV 
Any T 
Any N 
M1 
 
 
 
 
 
  

 
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APPENDIX V 
 
Dual Phase Pancreatic Imaging Protocol 
 
Dual phase pancreas CT protocol using iodinated intravenous contrast will be obtained at 2.5- or 3-mm slice thickness and, 
if possible, reconstructed to 1.25- or 0.625 mm slice thickness in addition to the 2.5-mm sections or 1.5- and 0.75-mm slice 
thickness in addition to the 3-mm sections. The two phases are during the phase of peak pancreatic enhancement and 
during portal venous enhancement and will be obtained of the entire abdomen. If CT cannot be obtained because of allergy 
to iodinated contrast, gadolinium-enhanced MRI will be utilized of the entire abdomen utilizing T1-, T2- and dynamically 
obtained T1-weighted sequences at a slice thickness of maximally 7 mm. If patient has history renal insufficiency or renal 
failure, and calculated GFR within 14 days prior to CT or MRI is < 30, non-contrast MRI will be utilized with T1- and T2- 
weighted sequences with a slice thickness not to exceed 7 mm. If MRI cannot be obtained (i.e., implanted electronic 
devices), unenhanced 2.5- or 3-mm sections of the abdomen will be obtained by CT without intravenous contrast. 
 
The timing of imaging after contrast administration: Bolus Tracking Technique 
The timing varies between the 16 and 64 detector scanners. For example, imaging of the entire abdomen during the 
pancreatic parenchymal phase, in a normal patient with normal cardiac circulation time, on a 16 would approximately begin 
at 36 seconds after the start of contrast injection and finish at 46 seconds. On the 64, it would begin at 40 seconds, and end 
at 45 seconds. (The pancreas is imaged during the same time period for both — note both terminate at 45–46 seconds). 
The second phase is at 60 seconds after the start of injection depending on the scanner (60 for 16) in a normal patient.  
 
A standard commercially available intravenous bolus tracking technique is recommended for use to control for variations 
in cardiac circulation time to ensure that images are obtained during the correct phases of contrast enhancement. As is 
standard practice, a cursor is placed in the aorta at the level of the origin of the celiac axis and is used to detect when 
contrast arrives in the abdominal aorta and raises the density value to 100 Hounsfield units. The 16 detector row scanner 
is instructed to begin scanning 16 seconds after that level is reached. Scanning of the abdomen is completed within 10 
seconds, and after a subsequent 14 second delay, the abdomen is imaged again during the portal venous phase. In a 
normal patient, scanning of the abdomen during the first phase would begin 36 seconds after the start of contrast injection, 
and scanning of the second phase would begin 60 seconds after contrast injection.  
 
In contrast, the 64 detector row scanner is instructed to begin 20 seconds after the 100 HU threshold is reached. Scanning 
of the abdomen is completed within five seconds, and after a subsequent delay of 15 seconds, the abdomen is imaged 
again during the portal venous phase. In a normal patient, scanning of the abdomen during the first phase would begin 40 
seconds after the start of contrast injection, and scanning of the second phase would begin 60 seconds after contrast 
injection. The differences in timing between the 16 and 64 detector scanner are designed so that imaging of the pancreas 
during the first phase is finished at approximately 45–46 seconds after the start of contrast injection. 

 
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Appendix VI 
Duodenal /Stomach Anatomy 
 
 
 
 
 

 
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Appendix VII-Glossary of Terms 
 
 
(MLQED2)-MLQ equivalent dose in 2 Gy fractions  
3DCRT-Three-dimensional conformal radiation therapy 
4DCT-Four-dimensional computed tomography  
5FU-5- fluorouracil 
ADC-apparent diffusion coefficient  
AE-adverse events  
AIDS-acquired immune deficiency syndrome  
ART-adaptive radiation therapy  
BED-biologically equivalent dose  
CFRT-conventionally fractionated radiation therapy 
cGy-centigray  
CPR-continuing progress report  
CR-complete responses  
CRT-chemoradiation 
CTC AE-Common Terminology Criteria for Adverse Events  
CT-computed tomography 
CTV-Clinical target volume 
DLT-dose-limiting toxicity  
DSMB -Data Safety Monitoring Board  
DWI-diffusion-weighted imaging  
ECOG-Eastern Cooperative Oncology Group 
FOLFIRINOX- FOL (folinic acid), F (fluorouracil) (5-FU), IRIN ( irinotecan) OX (oxaliplatin)  
GERCOR-Groupe Coopérateur  Multidisciplinaire en Oncologie  
GFR-glomerular filtration rate 
GITSG-GI tumor study group  
GTV-gross tumor volume 
Gy-Gray 
IGRT-image-guided radiation therapy  
IMRT- intensity-modulated radiation therapy  
IRB-internal review board  
ITV-internal target volumes  
KV conebeam CT-kilovoltage CAT scan 
MLQ-modified linear quadratic equation 
MRI-magnetic resonance imaging 
MU-monitor unit  
MV CT-megavoltage CT 
NTCP-normal tissue complication probability 
PET –Positron Emission Tomography 
PR-partial responses  
PTV-Planning Target Volume 
QUANTEC-Quantitative Analysis of Normal Tissue Effects in the Clinic  
R&V system-record and verify system 
RECIST- Revised Response Evaluation Criteria in Solid Tumors  
RTOG-Radiation Therapy Oncology Group  
RT-radiation therapy 
SBRT-stereotactic body radiation therapy 
SD-stable disease 
SAE-serious adverse events  
SIB-simultaneous integrated boost 
SMA-superior mesenteric artery 
SMF -Streptozocin, Mitomycin, and 5-FU  
SMV-superior mesenteric vein 
TD50-the dose corresponding to 50% complication probability for a uniformly irradiated whole organ