Phase II Study to Evaluate Stereotactic Body Radiation Therapy For Palliative Management of Unresectable Recurrent or Residual Pancreatic or Periampullary Adenocarcinoma
Phase: PHASE2
Conditions: Pancreatic Cancer, Periampullary Adenocarcinoma
Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

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PHASE II STUDY TO EVALUATE STEREOTACTIC BODY RADIATION 
THERAPY FOR PALLIATIVE MANAGEMENT OF UNRESECTABLE 
RECURRENT OR RESIDUAL PANCREATIC OR PERIAMPULLARY 
ADENOCARCINOMA 
Principal Investigator: 
Amol Narang, M.D.  
Weinberg 1440-Oncology 
401 North Broadway 
Baltimore, MD 21231-2410 
Phone: 410-502-3823 
Email:  anarang2@jhmi.edu 
Co-Investigators: 
Susannah Ellsworth M.D. 
Fariba Asrari, M.D. 
Elizabeth Jaffee, M.D. 
Nilofer S. Azad, M.D. 
John Cameron, M.D. 
Luis Diaz, M.D. 
Ross Donehower, M.D. 
Ralph Hruban, M.D. 
Daniel Laheru M.D.  
Dung Le, M.D. 
Christopher Wolfgang M.D., Ph.D. 
Lei Zheng, M.D., Ph.D. 
Timothy Pawlik, M.D, MPH 
Martin Makary, M.D. 
Matthew Weiss, M.D. 
Statistician: 
Hao Wang 
Hua-Ling Tsai 
Research Manager: 
Dana Kaplin 
Dkaplin1@jhmi.edu 
410-614-3950
NCT01781728

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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ........................................................................................................................................ 4 
SCHEMA ................................................................................................................................................................. 8 
1.  OBJECTIVES ..................................................................................................................................................... 9 
1.1. 
Primary Objective ................................................................................................................................ 9 
1.2. 
Secondary Objectives ........................................................................................................................... 9 
2.  BACKGROUND ................................................................................................................................................ 9 
2.1 
Natural History and Management of Pancreatic Cancer ...................................................................... 9 
2.2      
Current Adjuvant Management of Resectable Pancreatic Adenocarcinoma ....................................... 9 
2.3      
Current Neoadjuvant Management of Resectable Pancreatic Adenocarcinoma ................................ 11 
2.4      
Current Management of Locally Advanced, Unresectable Pancreatic  Adenocarcinoma ................. 12 
3. RATIONALE ..................................................................................................................................................... 12 
3.1 
Rationale for Radiotherapy in Treatment of Pancreatic and Periampullary Adenocarcinomas ......... 12 
3.2 
Rationale for Fractionated Stereotactic Radiotherapy........................................................................ 13 
3.3 
Rationale for Use in Treatment of Locally Progressive or Recurrent Disease .................................. 15 
4.  PATIENT SELECTION ................................................................................................................................... 17 
4.1 
Inclusion Criteria ................................................................................................................................ 17 
4.2 
Exclusion Criteria............................................................................................................................... 19 
5.  REGISTRATION PROCEDURES................................................................................................................... 19 
5.1 
General Guidelines ............................................................................................................................. 19 
5.2 
Registration Process ........................................................................................................................... 19 
6.  SBRT ADMINISTRATION AND RADIATION TREATMENT PLANNING ............................................. 19 
6.1 
Pre-Linac based SBRT Tests, Procedures, and Planning ................................................................... 19 
6.2 
General Concomitant Medication and Supportive Care Guidelines .................................................. 23 
6.3 
Duration of Study ............................................................................................................................... 25 
6.4 
Duration of Follow Up ....................................................................................................................... 24 
6.5 
Criteria for Removal from Study ....................................................................................................... 25 
6.6 
Alternatives ........................................................................................................................................ 25 
6.7 
Compensation..................................................................................................................................... 25 
7.  ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ........................................................... 25 
7.1 
Adverse Events and Potential Risks List ............................................................................................ 25 
7.2 
Reporting of Serious of Unexpected Adverse Events ........................................................................ 26 
7.3  
Definitions .......................................................................................................................................... 26 
8.  CORRELATIVE/SPECIAL STUDIES ............................................................................................................ 27 
8.1 
Laboratory Correlative Studies .......................................................................................................... 27 
8.2 
Collection of Pre and Post Treatment CT/PET Scans, Treatment Planning Scans, and Treatment 
Plans 
29 
9.  INVESTIGATOR RESOURCES .................................................................................................................. 30 
9.1 
Qualifications ..................................................................................................................................... 30 
9.2 
Use of Cancer Center Facilities.......................................................................................................... 30 
9.3 
Conflict of interest.............................................................................................................................. 30 
10.   
STUDY CALENDAR ................................................................................................................................ 31 

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11.  
MEASUREMENT OF EFFECT ................................................................................................................ 32 
11.1 
Anti-tumor Effect ............................................................................................................................... 32 
12. 
DATA REPORTING / REGULATORY CONSIDERATIONS ............................................................... 33 
12.1 
Monitoring Plan ................................................................................................................................. 33 
12.2 
Stopping Rules ................................................................................................................................... 34 
12.3 
Confidentiality ................................................................................................................................... 35 
13.  
STATISTICAL CONSIDERATIONS ....................................................................................................... 35 
13.1 
Endpoints ........................................................................................................................................... 35 
13.2 
Analysis Populations .......................................................................................................................... 35 
13.3 
Plan of Analysis ................................................................................................................................. 35 
13.4 
Sample Size ........................................................................................................................................ 36 
13.5 
Interim Analyses for Efficacy ............................................................................................................ 37 
13.6  
Data Analysis ..................................................................................................................................... 37 
REFERENCES ...................................................................................................................................................... 38 
Appendix I ............................................................................................................................................................. 43 
Appendix II ............................................................................................................................................................ 46 
Appendix III ........................................................................................................................................................... 47 

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PROTOCOL SYNOPSIS 
TITLE 
PHASE II STUDY TO EVALUATE 
STEREOTACTIC BODY RADIATION 
THERAPY (SBRT) FOR PALLIATIVE 
MANAGEMENT OF UNRESECTABLE 
RECURRENT OR RESIDUAL PANCREATIC 
OR PERIAMPULLARY ADENOCARCINOMA 
STUDY PHASE 
II 
INDICATION 
Unresectable recurrent or residual pancreatic or 
periampullary tumors 
PRIMARY OBJECTIVE 
• To evaluate rates of late (> 3 months after 
treatment) gastrointestinal toxicity following 
fractionated Linac based SBRT for pancreatic 
tumors. Toxicities of note include grade 2 or 
greater gastritis, enteritis, fistula, or ulcer and 
any other grade 3 or greater gastrointestinal 
toxicity. 
SECONDARY OBJECTIVES 
• To evaluate rates of acute (within 3 months of 
treatment) gastrointestinal toxicity following 
fractionated Linac based SBRT for pancreatic 
tumors. Toxicities of note include any grade 3 
or greater gastrointestinal toxicity. 
• To evaluate local progression free survival, 
overall survival, metastasis-free survival, and 
progression-free survival rates following Linac 
based SBRT in patients with unresectable 
recurrent or residual pancreatic or periampullary 
adenocarcinoma. 
• To evaluate the ability of Linac based SBRT to 
provide pain control among symptomatic 
patients as measured by pain medication 
requirement at 3, 6 and 12 months after 
treatment. 
• To evaluate the utility of FDG-PET for 
treatment planning and estimation of 
progression-free survival. 
• To develop and standardize Linac based SBRT 
delivery and dosimetric parameters. 
• To evaluate toxicity and outcomes among two 
cohorts of patients: a) patients with recurrent or 
residual disease after previous chemoradiation 
therapy, with or without surgery, who will be 
treated with 5 Gy x 5 and (b) patients with 
recurrent or residual disease after chemotherapy 
only, (with or without surgery), who will be 
treated with 6.6 Gy x 5.  
HYPOTHESES 
No standard treatment option has yet been 
established for patients with recurrent or residual 
disease after definitive treatment of pancreatic or 

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periampullary cancers (duodenal, ampullary, bile 
duct). Linac based stereotactic body radiation 
therapy (SBRT) administered in 1-3 fractions has 
been shown to be an effective treatment option for 
patients with unresectable, locally advanced 
pancreatic adenocarcinoma, achieving local control 
rates of 84-92% at one year. Associated late 
gastrointestinal toxicity rates have been reported to 
be 22-25% at 1 year. We hypothesize that similarly 
excellent local control rates (80-90% at one year) 
with a reasonable rate of toxicity (≤20%) can be 
achieved using Linac based SBRT delivered as 5 
Gy x 5 for patients with local failure after previous 
treatment with conventional chemoradiation 
therapy (CRT) with or without surgery and as 6.6 
Gy x 5 for radiation-naïve patients with local 
failure after previous treatment with surgery and/or 
chemotherapy. The toxicities of note for this trial 
are grade 2 and greater gastritis, fistula, enteritis, 
ulcer, or any other grade 3 or greater gastrointestinal 
toxicity.  
STUDY DESIGN 
Prospective, non-randomized, phase II study. 
PRIMARY ENDPOINT 
AND SECONDARY 
ENDPOINTS 
Primary Endpoint: 
• Late (> 3 months after treatment) grade 2 or 
gastritis, enteritis, fistula, and ulcer, or any 
other grade 3 or greater gastrointestinal 
toxicity. 
 
Secondary Endpoints: 
• Acute (within 3 months of treatment) grade 3 
or greater gastrointestinal toxicity. 
• Local progression free survival, progression-
free survival, metastasis-free survival, and 
overall survival rates at 3, 6, and 12 months 
after therapy. 
• Symptom control as measured by pain 
medication requirement at 3, 6, and 12 months 
after Linac based SBRT. 
• Change in pancreatic or periampullary tumor 
volume with FDG-PET/CT compared to CT 
scan. 
• Health-related quality of life (QoL) before and 
after SBRT. 
SAMPLE SIZE BY TREATMENT GROUP 
120 (60 in Cohort A, 60 in Cohort B; see inclusion 
criteria below for cohort definitions) 
SUMMARY OF SUBJECT ELIGIBILITY 
 

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CRITERIA 
INCLUSION CRITERIA 
• Age >18 years. 
• Karnofsky Performance Status >70% (see 
Appendix II). 
• Histologically confirmed pancreatic or 
periampullary adenocarcinoma; at least the 
majority of the histopathologic specimen 
must be identified as adenocarcinoma.  If 
previously diagnosed, recurrence can be 
based on imaging findings of recurrence. 
• Either: 
(a) 
Previously completed standard of 
care or protocol treatment for pancreatic or 
periampullary adenocarcinoma consisting of 
either surgical resection with 
neoadjuvant/adjuvant CRT for resectable 
disease or conventional CRT as definitive 
treatment for unresectable disease. These 
patients who have received prior radiation 
therapy will constitute Cohort A and will 
receive SBRT as 5 Gy x 5. 
OR  
(b) 
Previously initiated standard of care 
or protocol treatment for pancreatic or 
periampullary adenocarcinoma consisting of 
chemotherapy (without radiation) for 
unresectable disease or surgical resection 
with neoadjuvant/adjuvant chemotherapy 
(without radiation) for resectable disease. 
Patients who have not previously received 
radiation therapy will constitute Cohort B 
and will receive Linac based SBRT as 6.6 
Gy x 5. 
• 
Disease recurrence or residual disease at 
least 6 months after completing initial 
definitive therapy for patients who have 
received prior radiation and 3 months after 
initiating therapy for patients who have not 
received radiation. 
• 
Pancreatic or periampullary tumors must be 
less than 8 cm in greatest axial dimension at 
time of treatment planning. 
• 
No active infection requiring hospitalization 
• 
Patients must have acceptable organ and 
marrow function (see section 4.1.7). 
• 
Women who are not post-menopausal 
(as defined in Appendix III) should have a 
negative urine or serum pregnancy test. 
Women of childbearing potential must agree 
to use adequate contraception for the 
duration of study participation. 

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• Ability to understand and the willingness to 
sign a written informed consent document. 
• Life expectancy > 3 months. 
EXCLUSION CRITERIA 
• Presence of metastatic disease. 
• Infections requiring systemic 
antibiotic treatment. 
• Unable to understand or unwilling to sign a 
written informed consent document. 
• Life expectancy < 3 months. 
PROCEDURES 
Endoscopically guided fiducial placement with 
optional biopsies obtained at the time of fiducial 
placement. 
STATISTICAL CONSIDERATIONS 
See statistics section. 
 
 
 

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SCHEMA 
 
 
 
 
 
 
 
 
       
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patients who previously received standard 
of care or protocol treatment for 
pancreatic or periampullary 
adenocarcinoma that did involve radiation 
therapy, including: 
(a) surgical resection in combination 
with either neoadjuvant or 
adjuvant chemoradiation therapy 
(CRT) for resectable disease 
OR 
(b) definitive CRT for locally 
advanced, unresectable disease 
and who subsequently were found to have 
confirmed radiologic evidence of 
recurrent or residual disease and have 
previously completed radiation ≥ 6 
months prior to Linac based SBRT. 
LINAC BASED 
SBRT         
5 Gy x 5          
(over 1-2 weeks)* 
Cohort A                 
(recurrent or residual disease; did 
receive  previous RT) 
Patients who previously received standard 
of care or protocol treatment for pancreatic 
or periampullary adenocarcinoma that did 
not involve radiation therapy, including: 
(a) surgical resection in combination 
with either neoadjuvant or adjuvant 
chemotherapy for resectable 
disease 
OR 
(b) definitive chemotherapy for locally 
advanced, unresectable disease 
and who subsequently were found to have 
confirmed radiologic evidence of recurrent 
or residual disease and have previously 
initiated treatment ≥ 3 months prior to 
Linac based SBRT. 
LINAC BASED 
SBRT         
6.6 Gy x 5    
Cohort B                 
(recurrent or residual disease; did 
not receive previous RT) 
*It is recommended that patients in both cohorts discontinue any chemotherapy one week prior to 
Linac based SBRT and delay resumption of chemotherapy until 1 week following completion of 
Linac based SBRT. Patients must receive at least 2 consecutive radiation treatments per week if 
given over a 2 week period. 

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1.  OBJECTIVES 
1.1. 
Primary Objective 
To evaluate rates of late (> 3 months after treatment) grade 2 gastritis, enteritis, fistula, and 
ulcer, or any other grade 3 or greater gastrointestinal toxicity. 
1.2. 
Secondary Objectives 
1.2.1 
To evaluate rates of acute (within 3 months of treatment) grade 3 or greater 
gastrointestinal toxicity. 
1.2.2 
To determine rates of local progression free survival, overall survival, metastasis-
free survival, and progression-free survival in patients with recurrent or residual 
disease treated with fractionated Linac based SBRT. 
1.2.3 
To evaluate the utility of FDG-PET before and following treatment in predicting 
local progression. 
1.2.4 
To evaluate patient quality of life before and after Linac based SBRT. 
1.2.5 
To evaluate the ability of Linac based SBRT to provide pain control in symptomatic 
patients with pain related to a pancreatic tumor.  
1.2.6 
To further develop standardization of Linac based SBRT delivery and dosimetric 
parameters. 
1.2.7 
To compare outcomes among patients treated with fractionated Linac based SBRT 
delivered as 5 Gy x 5 (Cohort A of current protocol) or 6.6Gy X 5 (Cohort B of current 
protocol) with patients treated with 25 Gy X 1. 
 
2.  BACKGROUND 
2.1 
Natural History and Management of Pancreatic Cancer 
More than 40,000 individuals are diagnosed with pancreatic cancer annually in the United 
States. Despite aggressive combined modality treatment approaches, five-year survival of 
patients with pancreatic cancer is still less than 5% (1). Clearly, more innovative treatments 
are needed to improve survival in this group of patients. 
 
Surgical resection is considered to be the only potentially curative treatment option (2). 
However, the majority of pancreatic cancer patients do not have resectable disease at 
presentation.  More than 85% of patients have locally advanced or metastatic disease when 
initially diagnosed.   
2.2      Current Adjuvant Management of Resectable Pancreatic 
Adenocarcinoma 
Among the minority of patients who are able to undergo surgical resection, low median 
survival rates and cure rates imply the presence of residual local and/or systemic microscopic 
disease that may be amenable to adjuvant therapy. The standard of care for adjuvant therapy 
is controversial.  Adjuvant chemoradiation has been frequently studied due to high rates of 
positive margins and locoregional recurrences seen in surgical series.  The benefit of 5-
fluorouracil-based chemoradiation was first seen in a small, randomized trial performed by 
the Gastrointestinal Tumor Study Group (GITSG) (2). This study, published in 1985, 
randomized patients to observation versus postoperative therapy with concurrent 5-FU and 
split-course radiation (40Gy), followed by two years of adjuvant 5-FU. It showed a striking 
benefit in median survival and 5-year overall survival among patients undergoing 
chemoradiation despite the fact that there was no difference in locoregional control among 
the two arms. The EORTC performed a similar study that enrolle patients with either 

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

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

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strategy, therefore, is to combine neoadjuvant chemotherapy and/or radiation, surgical 
resection, and adjuvant chemotherapy and/or radiation to achieve the highest possible rate of 
long-term survival, though no RCTs have yet been done to conclusively prove the efficacy 
of this regimen. 
2.4      Current Management of Locally Advanced, Unresectable Pancreatic 
 
Adenocarcinoma 
First-line chemotherapy for locally advanced/metastatic pancreatic cancer is gemcitabine, a 
nucleoside analog. In the pivotal trial leading to FDA approval of this drug, patients with 
metastatic pancreatic cancer who were treated with gemcitabine had a modest improvement 
in survival compared to patients treated with 5-fluorouracil (5-FU) (3). The median survival 
improved from 4.41 months to 5.56 months. However, nearly 25% of patients receiving 
gemcitabine had clinical benefit, compared to 5% of patients receiving 5-FU.  In a recent 
meta-analysis, the addition of platinum analogs to gemcitabine demonstrated a survival 
benefit in patients with a good performance status. However, additional studies are necessary 
to determine which drugs are best combined with gemcitabine (4). 
 
A recent study compared full dose gemcitabine (1000 mg/m2) to a lower dose of gemcitabine 
(600 mg/m2) combined with standard fractionated radiation (50.4 Gy over 5.5 weeks) among 
patients with localized unresectable pancreatic cancer.  Although the study was closed prior 
to reaching its planned accrual, there was a significant improvement in survival in patients 
receiving combined gemcitabine and radiation compared to gemcitabine alone (5).  Objective 
responses were observed in 2.7% of patients in the gemcitabine alone arm (95% CI [0.09%, 
14.1%]) and in 8.8% of patients in the combined arm (95% CI [1.9%, 23.7%]). In this trial, 
the dose of gemcitabine was reduced to 600 mg/m2 with radiation, and patients required a 4 
week break prior to resuming full dose gemcitabine.  Grade IV toxicities, principally 
gastrointestinal and hematologic, was more common in the combined group (41.2 vs. 5.7%; 
p<0.0001). Although there was an improvement in survival, patients who received combined 
chemoradiation had substantially more toxicity compared to those who were treated with 
gemcitabine alone.  Thus, there is currently no consensus regarding standard of care for 
treatment of locally advanced, unresectable pancreatic carcinoma, but either chemotherapy 
alone or combined CRT can be considered appropriate in this setting. 
3. RATIONALE 
3.1 
Rationale for Radiotherapy in Treatment of Pancreatic and 
Periampullary Adenocarcinomas  
Radiation therapy is a widely accepted treatment for pancreatic cancer. The Gastrointestinal 
Tumor Study Group (GITSG) carried out a series of landmark studies demonstrating the 
effectiveness of radiation therapy as both adjuvant and definitive treatment in pancreatic 
cancer (6,7). Modern radiation treatments have increasingly used conformal fields and dose 
escalation to enhance tumor control (8, 9). Efforts to increase radiation dose to the pancreatic 
tumor without risking normal tissue injury have generally required relatively invasive 
techniques such as interstitial implantation of radioactive metals or intraoperative 
radiotherapy (IORT) (10, 29).  Historically, the local control rates for conventionally 
fractionated radiotherapy have ranged from 25-50%.  Local progression of pancreatic cancers 
can result in considerable morbidity, including gastric outlet obstruction, biliary obstruction, 
and pain (30). 
 
Periampullary tumors are also frequently treated with radiation therapy. Patients with 
periampullary tumors have also been included in this trial because of anatomic and 

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pathological similarities to patients with pancreatic cancer and the fact that the treatment 
paradigm for these cancers is similar to pancreatic cancer. Patients with periampullary tumors 
also have similar survival and recurrence patterns as patients with pancreatic cancers (31). 
Periampullary adenocarcinoma is a rare malignancy, comprising less than 1% of all digestive 
cancers and occurring at an annual age-adjusted incidence of only 0.3 cases per 100,000 
individuals (32). As a consequence of this low prevalence, few studies have been performed 
in this population, and patients who fail definitive therapy (surgical resection in association 
with neoadjuvant or adjuvant CRT/chemotherapy for resectable disease; conventional CRT 
or chemotherapy for unresectable disease) have limited options for further treatment (33,34). 
Unfortunately, even among patients with resectable periampullary adenocarcinoma, over 
50% will recur following definitive treatment (35). This trial, therefore, seeks to study SBRT 
as a means of providing patients with periampullary tumors with an additional treatment 
option in the case of locally recurrent or progressive disease.  
3.2 
Rationale for Fractionated Stereotactic Radiotherapy 
The mortality rate for pancreatic cancer approaches 100%. Current therapies provide only 
partial palliation of symptoms and slight prolongation of survival. More effective therapies 
are clearly needed. Several clinical trials have shown that Linac based SBRT has the potential 
to significantly improve progression-free survival of patients with pancreatic tumors, which 
could translate into both more effective palliation and longer patient survival.  
 
Koong et al. previously used the CyberknifeTM stereotactic radiosurgery system to 
demonstrate that a single dose of 25 Gy Linac based stereotactic body radiotherapy (SBRT) 
was feasible for patients with locally advanced pancreatic cancer (36).  Furthermore, this dose 
of radiation resulted in near 100% progression free survival and effectively palliated 
symptoms related to the local growth of pancreatic tumors. Based on this study, the same 
group also completed a phase II study assessing the efficacy of combining a standard five-
week course of chemoradiotherapy followed by a stereotactic radiosurgery boost to the 
primary tumor in patients with locally advanced pancreatic cancer. In this cohort of 19 
patients, 100% of tumors were without local progression.  However, all patients eventually 
developed metastases, with a median time to progression of 5.5 weeks. 
 
More recently, another phase II study treated locally advanced pancreatic cancer patients with 
gemcitabine followed by 25 Gy of Linac based SBRT delivered with Cyberknife and 
maintenance gemcitabine chemotherapy.  In this study, the excellent progression free survival 
was confirmed from previous studies (81%).  The median overall survival was 11.4 months, 
median time to progression was 9.7 months and the 1 year survival was 50% (37). There were 
no significant acute GI toxicities however, of the 15 patients alive >6 months after Linac 
based SBRT, 7 (47%) experienced Grade 2 or greater GI toxicity, with 2 (13%) of the 15 
experiencing Grade 3 or greater GI toxicity. 
 
Linac based SBRT is delivered using linear accelerators and image-guided radiation therapy 
(IGRT). These machines combine a conventional high-energy linear accelerator with a kV 
imager capable of volumetric, cone beam CT (CBCT). Because of these innovations, it is 
possible to deliver highly accurate, stereotactic radiation treatments. 
 
A recent protocol evaluated full dose gemcitabine before and after single fraction Linac based 
SBRT.  Preliminary results indicate that the local progression free survival was comparable 
to what was previously observed (90%) with CyberKnife treatment (personal 
communication).  All acute toxicity was grade 2 or less; however, a minority of patients 
developed late duodenal ulcers (15%), including 1 perforation (5%) with a single fraction of 
Linac based SBRT.  Therefore, LInac based SBRT appears to achieve local control of 

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pancreatic tumors in a large majority of patients with reasonable rates of toxicity, suggesting 
that Linac based SBRT would be an effective treatment option for patients with locally 
recurrent disease, as we propose in this protocol.  
 
To date, Stanford has treated more than 150 patients with Linac based SBRT, and this 
treatment has resulted in local control rates of >90% with acceptable acute GI toxicity. We 
predict that this treatment will not adversely impact patients’ quality of life. Although QOL 
measures have not been thoroughly studied among pancreatic cancer patients treated with 
Linac based SBRT, the majority of patients treated with Linac based SBRT appear to derive a 
clinical benefit as assessed by decreased pain, decreased fatigue, and increased weight. A 
single fraction of Linac based SBRT (25 Gy x 1) has resulted in excellent tumor control.  
However, close to 50% of these patients developed late duodenal toxicity within one year, 
primarily because of the proximity of the duodenum to the pancreas. 
 
We hypothesize that delivering fractionated Linac based SBRT (5 Gy x 5 or 6.6 Gy x 5) 
instead of single fraction treatment will result in equivalent tumor control with less late 
toxicity (≤20%).  At this time, there is no clear consensus regarding an optimal fractionation 
schedule for unresectable pancreas cancer (38,39).  Based on a recent study, this fractionation 
schedule is predicted to provide equivalent tumor control probability to 25 Gy x 1 while 
resulting in less normal tissue toxicity (40). 
 
Although we believe this schedule (5 Gy x 5 or 6.6 Gy x 5) will result in good tumor control 
and acceptable toxicity, the potential clinical efficacy of this short-course, hypofractionated 
regimen is unknown. The choice of this regimen as a potentially effective approach for 
unresectable pancreatic cancer treatment is based on three observations. First, a similar 
schedule (5 Gy x 5) has been widely and efficaciously used in the neoadjuvant setting for 
rectal cancer, although a much larger field is used.  Additionally, a series of patients with 
resectable pancreatic lesions treated at the M.D. Anderson Cancer Center strongly suggest 
that a 5-FU based chemoradiation regimen consisting of 30 Gy in 10 fractions over 2 weeks 
reduces treatment time and toxicity compared with a regimen consisting of 50.4 Gy in 28 
fractions over 5 to 6 weeks without compromising overall survival or local control. Hong et 
al. from Massachusetts General Hospital have reported on a neoadjuvant regimen delivering 
5 Gy x 5 to the pancreatic tumor plus adjacent lymph nodes using proton beam radiation (41). 
They show this regimen to be safe, with no instances of dose limiting toxicity observed and 
only 4 of 15 patients developing grade 3 toxicity (no patients experienced grade 4 toxicity).  
The phase I feasibility study outlined in this protocol proposes a 5 Gy x 5 (patients who 
previously received radiotherapy) or 6.6 Gy x 5 (radiation-naïve patients) fractionation 
schedule treating the region of local recurrence or unresectable pancreatic tumor plus a 3 mm 
margin.  These volumes will be substantially smaller than the regimens outlined above for 
rectal and pancreatic cancer, likely leading to a lesser degree of toxicity. Using the linear-
quadratic formulation, the biologically equivalent dose (BED) of the two proposed 
fractionation schedules are given in comparison to other commonly used schemes (table 1). 
While the BED for the 5 Gy x 5 schedule (early/late 37.5/66.7) must necessarily be lower 
because it will be used in patients who have already been treated with radiation to the 
pancreatic region, that of the proposed 6.6 Gy x 5 schedule (BED early/late 54.8/105.6) 
closely approximates that of standard chemoradiation (BED early/late 60/83.3), but without 
concurrent chemotherapy and treating a smaller tumor margin (0.3 cm vs. ~2 cm). 
Furthermore, the proposed 6.6 Gy x 5 fractionation schedule has a much lower late BED 
(105.6 vs. 233.3) with a similar early BED (54.8 vs. 87.5) as the previous 25 Gy x 1 regimen. 
 
Table 1: 

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NodesTx 
Chemo 
BED early 
BED late 
 
 
 
a/b=10 
a/b=-3 
50.4 
Yes 
Yes 
60 
83.3 
30 Gy/10 
Yes 
Yes 
39 
60 
25 Gy/5 
No 
No 
37.5 
66.7 
33 Gy/5 
No 
No 
54.8 
105.6 
25 Gy/1 
No 
No 
87.5 
233.3 
 
In this study, we will refine our current understanding of radiation tolerance of the pancreas 
and adjacent organs, thereby making it possible to treat future patients more safely and 
aggressively. 
 
 
The major benefit of Linac based SBRT/chemotherapy for unresectable, locally recurrent 
and locally progressive pancreatic and periampullary tumors is improved local control and 
palliation of symptoms related to local progression of these tumors. In addition, radiosurgical 
ablation of the tumor at the primary site can theoretically prevent distant seeding from the 
pancreatic tumor itself. Ultimately, these improvements in the treatment of pancreatic and 
periampullary cancer may translate into an improved quality of life and overall survival. 
 
Quality of life will be assessed using the European Organization for Research and Treatment 
in Cancer quality of life core cancer questionnaire with the pancreatic cancer module 
(EORTC QLQ-C30/PAN26).  The EORTC QLQ-C30 is a multidimensional, 30-item 
questionnaire, which assesses five functional scales (physical, role, cognitive, emotional, and 
social), three symptom scales (fatigue, pain, and nausea/vomiting), a global health/QOL 
scale, as well as 6 single items (42).  The EORTC QLQ-PAN26 supplements the core 
questionnaire with 26 items specific for patients with pancreatic cancer (43,44). These 
instruments have been validated in patients receiving treatment for metastatic and resected 
pancreatic cancer and are sensitive to identify treatment related changes in quality of life. The 
quality of life of patients in this study will be compared to historical cohorts of patients treated 
with conventional chemoradiation at Johns Hopkins. 
 
3.3 
Rationale for Use in Treatment of Locally Progressive or Recurrent 
Disease 
The development of recurrent pancreatic cancer after definitive treatment with surgery, 
radiation, chemotherapy, or a combination of these universally portends a dismal prognosis, 
with the 5-year survival for such patients being 5.6% or less (45). Unfortunately, this scenario 
is not uncommon; even among the small number of patients (10-15%) able to undergo 
potentially curative surgical resection, more than 80% subsequently develop recurrent disease 
(46). Among the majority of patients with pancreatic cancer who present with unresectable 
disease, chemoradiation is able to transiently stabilize the disease in some patients and to 
prolong median survival to 8-14 months (47-50). However, virtually 100% of patients 
develop disease progression and succumb within 3 years (51-55).  
 
 
The pattern of recurrence in pancreatic cancer is well known (11,18,56,57) and is similar to 
that of periampullary adenocarcinoma (35). Following resection, 71-77% develop distant 
metastases within 2 years, often accompanied by concurrent locoregional recurrence, while 
up to 30% (58, 59) exhibit isolated locoregional recurrence (60,61). Patients who develop 
combined distant/locoregional recurrence have a median survival of 3 months from the time 

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of recurrence, while those with isolated locoregional recurrence have a median survival of 7 
months (60). Locoregional recurrence is, therefore, a common and serious problem both in 
the setting of metastatic disease and as an isolated entity. Symptomatic manifestations include 
pain, gastric outlet/small bowel obstruction, portal hypertension, biliary obstruction, and 
malnutrition (61). Although survival is determined chiefly by systemic disease control, local 
control is an important factor contributing to quality of life (62,63). The symptoms associated 
with local recurrence require a mode of treatment that is swift and efficacious in order to 
restore patient quality of life and give patients the best chance at greater overall survival.  
 
 
To date, no studies involving radiotherapy have been performed that primarily focus on this 
specific population of patients who have developed local failure after previous standard of 
care or protocol therapy for pancreatic or periampullary adenocarcinoma. Consequently, no 
standard treatment option has yet been defined. Current options include surgical re-
exploration with possible re-resection, palliative chemotherapy or conventionally 
fractionated chemoradiotherapy (CRT), and best supportive care.  Each of these has 
significant drawbacks, including: high degree of invasiveness and morbidity in the case of 
surgical re-resection (41,64); slow onset of effect, substantial systemic toxicity, and inferior 
local control rates (71.1%) with palliative chemotherapy or conventionally fractionated CRT 
(65); and lack of efficacy and diminished overall survival with best supportive care alone.   
 
We propose that the drawbacks associated with the current treatment options above can be 
circumvented or mitigated by the use of fractionated SBRT, while simultaneously achieving 
excellent rates of local control and symptom palliation.  Linac based SBRT is a non-invasive 
means of achieving effective local control in a large majority of patients (81 to nearly 100% 
at one year in previous studies) (36,37,66,67).  Additionally, we propose to deliver the Linac 
based SBRT in 5 fractions over the course of 1-2 weeks, allowing for swift alleviation of 
symptoms associated with local tumor recurrence/progression. Conventionally fractionated 
radiation therapy (RT), on the other hand, delivers a similar BED (see table 1 in section 3.2) 
over a much longer period of 5-6 weeks. Furthermore, the tighter margins used in Linac based 
SBRT (0.2-0.3 cm) compared to conventional RT (2-3 cm) may result in less gastrointestinal 
toxicity (68). Therefore, we suggest that Linac based SBRT avoids the drawbacks associated 
with other existing treatment options for patients with recurrent pancreatic adenocarcinoma; 
that is, Linac based SBRT is effective, non-invasive, swift to take effect, and associated with 
a relatively mild toxicity profile. 
 
Two recent studies support this assertion. In 2009, Chang et al. reported on the use of Linac 
based SBRT delivered as 25 Gy in a single fraction for patients with unresectable pancreatic 
adenocarcinoma (67). Of the 77 patients, 58% had locally advanced disease and 14% had 
medically inoperable disease, but the remainder were similar to our population in that they 
had either low-burden metastatic disease (19%) or locally recurrent disease (8%). Results 
were encouraging, with rates of freedom from local progression at 6 and 12 months of 91% 
and 84%, respectively.  Overall survival at 6 and 12 months was 56% and 21%, respectively. 
Only 5% of patients experienced grade 2 or greater acute toxicity, 4% experienced grade 2 
late toxicity, and 9% experienced grade 3 or greater late toxicity. Rates of grade 2 or greater 
late toxicity were 11% and 25% at 6 and 12 months, respectively.  
 
In 2010, Didolkar et al. reported on the use of Linac based SBRT doses ranging from 15 to 
30 Gy delivered in 3 equal fractions, with mean dose of 25.5 Gy over 3 days (66). Eighty-
five patients were studied; the majority (71 patients) had locally advanced disease, but a small 
number (14 patients) were included who were similar to our population in that they had 
locally recurrent disease. Results were again encouraging, with 78 patients (92%) achieving 
complete response, partial response, or stable disease for a duration of 3-36 months with a 

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median of 8 months. Pain relief was noted in the vast majority of patients lasting for 18-24 
weeks. Median survival from time of Linac based SBRT was 8.65 months, which is 
comparable to or better than reported results for locally advanced pancreatic cancer (69-72). 
Nineteen patients (22.4%) developed grade 3-4 gastrointestinal toxicity, consisting of 
duodenitis, gastritis, and diarrhea in order of decreasing frequency. One patient developed 
renal failure. 
 
We recently presented the preliminary results of our phase II multi-center trial of gemcitabine 
(GEM) and fractionated Linac based SBRT to determine if a high rate of LPFS with reduced 
toxicity could be achieved. After multidisciplinary review, 32 pts with locally advanced PDA 
received GEM in sequence with Linac based SBRT (6.6 Gy in 5 consecutive daily fractions, 
33 Gy total). LPFS, metastasis free survival (MFS), and overall survival (OS) were measured 
from date of tissue diagnosis. Objective tumor response (OTR) was assessed by 
RECIST/PERCIST. EORTC QLQ-C30/PAN26 questionnaires were used to measure QOL. 
Median f-up was 12 mos (range, 2-23). Mean age was 69.9 yrs (SD, 9.8) and 62% were male. 
Patients received a mean of 2.2 (SD, 1.0) GEM doses prior to SBRT and 8.3 (SD, 5.6) doses 
total. All pts completed SBRT. Median OS was 15.9 months (95% CI, 12.7-18.8). 
Stratification by CA19-9 > or < 90 at diagnosis yielded a hazard ratio of 6.2 for > 90 
(p=0.021). Median LPFS has not been reached and median MFS was 10.2 mos (95% CI, 2.9-
17.5). LPFS rate at 1 year was 87%. OTR on CT was seen in 41%, while 41% had stable 
disease and 18% progressed.  Tumor metabolic activity decreased in 17/18 patients with 
pre/post- Linac based SBRT PET available. Mean peak SUV was 4.0 pre- Linac based SBRT 
versus 2.4 post- Linac based SBRT (p=0.002). Median CA19-9 was reduced from 124.7 prior 
to SBRT to 43.9 afterwards. Acute toxicity included: grade 2 anorexia (37%), fatigue (28%), 
nausea (22%), abd pain (19%), weight loss (9%), diarrhea (3%); gr 3 nausea (9%); and gr 4 
nausea (6%). Late gr ≥3 GI toxicity was seen in 9%.  Mean QOL score 4 wks post-Linac 
based SBRT was similar to baseline (p=0.38). At 6 mos there was a trend towards improved 
QOL (p=0.07).  Overall, fractionated Linac based SBRT with GEM achieved high rates of 
LPFS and tumor response. Minimal grade ≥3 acute and late toxicity was observed. Linac 
based SBRT is more likely to benefit patients with Ca-19-9 <90.  A combination of Linac 
based  SBRT with more aggressive chemotherapy may further improve outcomes.  
 
Considering the difficulty of surgical re-exploration due to extensive adhesions after previous 
resection, the risks of surgery and general anesthesia for patients who often have impaired 
performance status, and the prolonged time course and inferior local control associated with 
conventional CRT, we propose that SBRT may be a viable alternative treatment option for 
patients who have failed other modes of therapy through local recurrence or local progression. 
The paucity of studies focusing on this population and lack of a standardized treatment 
paradigm for these patients underscore the need for further investigation. The recent studies 
delineated above suggest that Linac based SBRT is a safe and promising therapeutic option 
for pancreatic and periampullary cancers that merits further study in the specific patient 
population that will be treated using this protocol. 
4.  PATIENT SELECTION 
4.1 
Inclusion Criteria 
4.1.1 
Age >18 years. 
4.1.2 
Karnofsky Performance Status >70% (see Appendix II).  
4.1.3 
Histologically confirmed adenocarcinoma of the pancreas or ampulla of Vater; at least 
the majority of the histopathologic specimen must be identified as adenocarcinoma as 
opposed to another histologic subtype. 
 

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*If histological confirmation of adenocarcinoma cannot be obtained by biopsy, the 
following procedures may be employed: 
4.1.3.1 Attempt a repeat biopsy to obtain a diagnosis. 
4.1.3.2 Present the case at JHU tumor board and if the candidate has one of the 
following: a rising CA 19-9 or radiographic evidence of recurrence on 
MRI, CT, and/or PET scan then the patient can be considered for treatment 
on protocol. 
However, if these objectives cannot be met, the patient will not be a candidate. 
 
4.1.4 
Pancreatic or periampullary tumors must be less than 8.0 cm in greatest axial 
dimension at the time of treatment planning. 
4.1.5  Either: 
 
 
Patients who have received RT: Previously (≥6 months before retreatment) 
completed treatment for pancreatic or periampullary adenocarcinoma consisting of 
either surgical resection with neoadjuvant/adjuvant conventional CRT for resectable 
disease or conventional CRT as definitive treatment for unresectable disease. These 
patients who have received prior radiation therapy will constitute Cohort A and will 
receive SBRT as 5 Gy x 5. 
 
*patients may be receiving continued chemotherapy post initial CRT. 
 
OR  
 
Patients who have not received RT: Previously (≥3 months before retreatment) 
initiated treatment for pancreatic or periampullary adenocarcinoma consisting of 
chemotherapy alone for unresectable disease or surgical resection with 
neoadjuvant/adjuvant chemotherapy for resectable disease. These patients who have 
not received prior radiation therapy will constitute Cohort B and will receive SBRT 
as 6.6 Gy x 5. 
 
*patients must have attempted chemotherapy upon initial diagnosis.  
 
4.1.6 
Patients must have acceptable organ and marrow function as defined below (within 
2 weeks prior to radiotherapy): 
• Leukocytes >2,000/µL 
• Absolute neutrophil count >1,000/µL 
• Platelets >75,000/µL 
• Total Bilirubin ≤1.5X normal institutional limits 
• AST(SGOT)/ALT(SGPT) <2.5X institutional upper limit of normal 
• Creatinine ≤ institutional upper limit of normal 
 
 OR 
 
• Creatinine clearance >60 mL/min/1.73 m2  for patients 
with creatinine levels above  institutional normal 

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4.1.7 
Ability to understand and the willingness to sign a written informed consent 
document. 
4.1.8 
Must be a patient to be treated with SBRT only at Johns Hopkins Hospital. 
4.1.9 
Life expectancy > 3 months. 
4.1.10 Patient must be able to have fiducials placed. If not, the tumor must be posterior 
and adjacent to the aorta and treatment will only be permitted at the discretion of 
the Principal Investigator. 
 
4.2 
Exclusion Criteria 
4.2.1  Children (< 18 years) are excluded because pancreatic and periampullary tumors 
rarely occur in this age group. Furthermore, treatment requires a great deal of patient 
cooperation including the ability to lie still for several hours in an isolated room. 
4.2.2  Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection (or infections requiring systemic antibiotic treatment), symptomatic 
congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric 
illness/social situations that would limit compliance with study requirements. 
4.2.3  Any concurrent malignancy other than non-melanoma skin cancer, non-invasive 
bladder cancer, early stage prostate cancer, or carcinoma in situ of the cervix.  
Patients with a previous non-pancreatic, non-periampullary malignancy without 
evidence of disease for > 5 years will be allowed to enter the trial. 
4.2.4  Pregnant and breastfeeding women are excluded as are women of child-bearing 
potential who are unwilling or unable to use an acceptable method of birth control 
(hormonal or barrier method of birth control; abstinence) to avoid pregnancy for the 
duration of the study.    Should a woman become pregnant or suspect she is pregnant 
while participating in this study, she should inform her treating physician 
immediately. 
4.2.5  Women who are not post-menopausal (as defined in Appendix III) and have a 
positive urine or serum pregnancy test or refuse to take a pregnancy test. 
4.2.6  Patients with a life expectancy of < 3 months. 
 
 
4.2.7 
Patients with metastatic disease. 
5.  REGISTRATION PROCEDURES 
5.1 
General Guidelines 
Subjects will be identified per the recommendation of surgeons or GI Combined Modality 
Tumor Board or equivalent combined modality assessment.  Subjects will be recruited 
through self-referral and the advice of their attending physician.  No advertisement will be 
used to recruit subjects. 
5.2 
Registration Process 
A member of the research team (most likely the research coordinator or research nurse) will 
enroll the patient into the trial.  Subjects will be entered into the patient database at Johns 
Hopkins Hospital. Consent will be obtained after a clear and thorough discussion between 
the patient and the principal investigator or any of the co-investigators in clinic. Any patients 
that are deemed by the principal investigator or co-investigators to be mentally or physically 
incapable of consent will not be included in the study. 
6.  SBRT ADMINISTRATION AND RADIATION TREATMENT PLANNING 
6.1 
Pre-Linac based SBRT Tests, Procedures, and Planning 
The following will be completed prior to Linac based SBRT: 

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a. 
Medical history and clinical examination. 
b. 
CBC with differential, Chemistry Panel, CA19-9.   
c. 
Gold fiducial seed placement percutaneously, intraoperatively, or under endoscopic 
ultrasound guidance, which may be performed prior to enrollment. 
d. 
Pathologic confirmation of malignancy. (Core biopsies during gold fiducial placement 
as needed or optional). 
e. 
CT Pancreas or C/A/P scan required; FDG-PET or FDG-PET/CT (dual phase) 
recommended at the discretion of the treating physician.  
f. 
Signed informed consent document. 
g. 
Baseline collection of EORTC QLQ C-30/ PAN26 QOL. 
h. 
Optional whole body dynamic PET/CT 
 
6.1.1 
Fiducials 
Treatment on this protocol requires placement of 1-5 gold (99.9% pure, 1-5 mm 
length, or visicoils) fiducials for targeting purposes.  The fiducials will be used as 
surrogates for targeting the daily tumor position during treatment. The fiducials will 
be placed directly into the tumor and/or periphery under endoscopic ultrasound or 
CT guidance.  When possible, clips or fiducials will also be placed in the proximal 
duodenum directly adjacent to the pancreatic tumor.  Fiducials may be implanted 
prior to enrollment as this is an acceptable standard of care procedure for any patient 
receiving radiotherapy for locally advanced pancreatic or periampullary cancer. 
Also, if a patient had an attempted surgical resection that was aborted, fiducials may 
have been implanted intraoperatively, which is also allowable prior to study 
enrollment. 
 
 
 
If fiducials are not placed intraoperatively and/or prior to enrollment, placement will 
be done and is expected to be done on an outpatient basis.  In rare occurrences when 
fiducials/clips cannot be placed, patients may be treated at the discretion of the PI. 
 
6.1.2 
Simulation 
1) Simulation should be done following placement of fiducials; however, this may 
vary and is at the discretion of the principal investigator. 
2) Typically, patients will be positioned supine in an Alpha Cradle or equivalent 
immobilization device that will be custom-made for each patient. 
3) Standard free-breathing CT and respiratory-correlated 4-D pancreatic protocol 
CT will be obtained on each patient. The 4D-CT scan will be used for 
characterizing target motion during quiet respiration. For more accurate tumor 
delineation, an arterial phase pancreatic protocol CT may be obtained (typically 
during expiration breath hold, 1.25 mm slices). Fiducial to fiducial fusions 
between these scans should be utilized whenever possible.  The simulation scan 
should include T4/T5 to L5/S1 (upper abdomen). 
4) A research dMRI may be conducted at the time of simulation. In order to derive 
a set of 4D anatomic images that are directly comparable to 4D-CT, the 
Department of Radiation Oncology has developed a retrospective, slice-
stacking, sorting technique that relies on a respiratory trace collected 
simultaneously with multi-slice 2D dMRI sequences (bSSFP and HASTE). 
The final rendered “4D-MRI,” or set of phase-binned 3D-MR volumes, 
represents a statistically-averaged breathing cycle over the long-duration 
imaging session. Because this frame-averaging approach can result in image 
blurring in the context of breathing variability, secondary anatomic-based 
sorting methods are employed to improve on image quality (contrast). Further, 

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for each imaged slice location and breathing phase bin a sufficiently large 
number of samples permits derivation of meaningful, image-based strategies to 
convey variability information, such as via rendering a corresponding “4D-
MRI standard deviation” image. This method is independent of the imaging 
sequence employed and is generically suitable for multiple sites of disease. 
5) IV and oral contrast must be used for simulation, unless the patient has an 
allergy that cannot be adequately premedicated. In these situations, the plan 
should be fused with an IV contrast CT scan or MRI (ideally in a similar 
treatment position). 
 
6) Motion management can be addressed using respiratory gating, breath-hold, 
respiratory tracking, or abdominal compression. 
 Specialized compression 
belts may be utilized for some 
patients. They come in 4 sizes: S, M, L, and 
XL.  Each belt has an adjustable pressure cuff which can be used to reduce 
breathing motion.  Fluoroscopy is used to assess motion of implanted gold 
markers before and after compression.  The goal is to reduce motion from 
typically 11-22 mm peak to less than 5 mm.  If the  fiducial motion cannot be 
decreased to 5 mm or less, then respiratory gating using either the Varian 
Respiratory Management (RPM) system or the Elekta Active Breathing 
Coordinator (ABC) will be utilized for treatment delivery. Prior to simulation, 
standard guidelines will be followed. 
7) As long as the specified dosimetric parameters for SBRT are reached, patients 
may be treated on any IGRT-enabled machine. 
8) All patients must start Linac based SBRT within 4  weeks of the simulation 
scan. 
 
6.1.3 
Treatment Planning 
1) When available, an FDG-PET scan is preferred for treatment planning purposes 
and will be acquired on a flat table top with the same immobilization devices 
used for the treatment planning CT simulation. 
2) An SBRT treatment plan will be developed using Pinnacle based on tumor 
geometry and location. Institutional standards for radiation quality assurance 
and radiation delivery will be utilized. 
3) The tumor volume (GTV), as identified on the treatment planning CT, will be 
contoured by an attending physician from Johns Hopkins Hospital.  The final 
GTV will be defined by the attending radiation oncologist after reviewing the 
diagnostic CT, respiratory-correlated 4D-CT scan, pancreas protocol CT, 
and/or the FDG-PET/CT scan. These scans will be used to define the ITV 
(internal target volume).  The final PTV (planning treatment volume) 
expansion will consist of an additional 2-3mm of margin expansion, except if 
the margin results in expansion into the duodenum or stomach. In these cases, 
margin expansion is allowed to be non-uniform. The dose will be prescribed to 
the isodose line that completely surrounds the  
PTV. It is recommended 
that 6-12 co-planar fields be used in the radiation treatment plan. 
4) Contours of the fiducials used for target localization will be generated on the 
applicable image sets, to be used for patient setup on treatment. 
5) Radiation dose to the adjacent normal tissue will be minimized. Based on an 
analysis of duodenal toxicity representing pooled data from 3 previous 
prospective studies, the following dose constraints must be met: V15<9cc, 
V20<3cc.  The duodenum (duo@PTV) as defined for these dosing parameters 
includes the entire duodenum on the same axial plane as the PTV and 
duodenum 1 cm above and 1 cm below the PTV.  In patients who have 

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undergone 
pancreaticoduodenectomy, 
the 
regions 
of 
the 
pancreaticojejunostomy, gastrojejunostomy, and hepaticojejunostomy that lie 
1 cm above or below or lateral to the PTV will also be delineated as structures 
of interest. V15  and V20 are defined as the percent volume receiving 15 Gy 
and 20 Gy, respectively.  No more than 1cc of the proximal duodenum or 
proximal stomach may exceed 33 Gy for cohort B (25 Gy for cohort A, re-
irradiation patients).  The remainder of the normal tissues will be limited as 
follows: 
• 
Liver (excluding tumor):  50% should be limited to <12 Gy (<8 Gy for 
cohort A-re-irradiation patients) 
• 
Kidney:  Combined volume for both should have 75% <12 Gy (<8 Gy 
for cohort A-re-irradiation patients) 
• 
Stomach and duodenum:  V15<9cc (V12<9 cc for cohort A) and 
V20<3cc (V15<3 cc for cohort A).  50% should be limited to <12 Gy 
(<8 Gy for cohort A) (no more than 1 cc of proximal stomach can receive 
>33 Gy for cohort B, (no more than 1 cc of proximal stomach can receive 
>25 Gy for cohort A, re-irradiation patients) 
• 
Spinal Cord: no more than 1cc can receive >8 Gy (>6 Gy for cohort A). 
6) No more than 1cc of the PTV can receive >130% of the prescription dose 
(4290cGy for 6.6Gy x 5; 3250cGy for 5Gyx5, cohort A). 
7) Greater than 90% of the PTV should receive 100% of the prescription dose 
(3300cGy for 6.6Gy x 5; 2500cGy for 5Gyx5). 
8) If above constraints cannot be achieved, then 100% of the GTV must receive 
at least 25 Gy (20 Gy for cohort A) (an allowed minor deviation, which will be 
documented). 
 
If this constraint cannot be met, the patient should be removed from the 
protocol. 
 
6.1.4 
Linac based SBRT Treatment Delivery 
Patients will receive 5 fractions of 5 Gy or 6.6 Gy delivered over a five-day period, 
as delineated above, based on whether or not they have received prior radiation 
therapy to the pancreatic region.  Ideally all 5 fractions should be delivered Monday 
through Friday; however, treatment may be delivered over 2 weeks, as long as the 
patient receives at least 2 fractions per week. 
 
Treatment Delivery (LINAC-based): 
1) Initial patient positioning will be based on volumetric kV (cone-beam CT) 
imaging with shifts to bony anatomy as appropriate. 
2) Orthogonal kV/MV or kV/kV projection imaging will be used to verify the 
location of the fiducials prior to delivery of first  
treatment 
beam. 
A 
secondary shift based on the location of fiducials may be utilized, as indicated 
by the position of the fiducials.  For free-breathing treatments, kV fluoroscopic 
images should be obtained to confirm the anticipated position of these fiducials 
during the entire respiratory cycle. 
3) Active monitoring of treatment delivery accuracy will be accomplished using 
kV and/or MV projection imaging, either immediately before or during all (or 
a subset of) treatment fields. 

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4) Patient-specific dosimetric quality assurance (QA) will be performed as per 
standard practice in the Department of Radiation Oncology and Molecular 
Radiation Sciences at Johns Hopkins Hospital. 
 
6.1.5 
Post-Linac based SBRT Follow-Up 
Following Linac based SBRT, all patients will be monitored clinically and with serial 
imaging (CT scans and/or PET/CT if possible and as deemed necessary by the treating 
physician). 
 
A detailed medical history with physical examination and quality of life assessment 
will be performed at 4-6 weeks, 4 months, 6 months, 9 months and 1 year after 
radiation treatment. 
 
In years 2-5, the follow up interval will be every 3-6 months, as determined by the 
principal investigator.  Follow up intervals may also be more frequent as indicated 
clinically. A complete blood count (CBC) with differential, comprehensive 
chemistry panel, tumor marker studies, and quality of life assessment will be 
performed at each follow-up interval.   
6.2 
General Concomitant Medication and Supportive Care Guidelines 
6.2.1 
Antidiarrheals and Anti-emetics 
For symptoms of diarrhea and/or abdominal cramping, patients will be instructed to 
take anti-diarrheals. Additional antidiarrheal measures may be used at the discretion 
of the treating physician.  Patients should be instructed to increase fluid intake to help 
maintain fluid and electrolyte balance during episodes of diarrhea. 
 
For symptoms of nausea and vomiting, anti-emics will be given one hour prior to 
Linac based SBRT and for up to 5 days following Linac basedSBRT on an as-needed 
basis. Additionally, patients will be instructed to increase fluid intake. 
 
All patients will be prescribed proton pump inhibitors (PPIs), which should begin by 
the start of Linac based SBRT and continue for a minimum of 6 months following 
Linac based SBRT. 
 
6.2.2 
Other Concomitant Medications 
Therapies considered necessary for the patient's well being may be given at the 
discretion of the investigator.  Other concomitant medications should be avoided 
except for analgesics, chronic treatments for concomitant medical conditions, or 
agents required for life-threatening medical problems. Specifically, if the patient is 
being treated with chemotherapy, it is recommended that chemotherapy be 
discontinued at least one week prior to initiation of Linac based SBRT and that 
resumption of chemotherapy be delayed for at least one week following the 
conclusion of Linac based SBRT.  In general, prescription of these medications 
will be presided over by the patient’s attending medical oncologist. 
 
6.2.3 
Supportive Care Guidelines 
All commonly accepted supportive care guidelines will be used. 
 
6.2.4 
Use of Radioisotopes/Rad Machines 
Stereotactic radiotherapy will be performed using Linac based radiation machines. 
The radiation treatment plan will be designed to use multiple beams of radiation to 

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concentrate large doses of radiation within a tumor. The Linac machines are equipped 
with cone beam CT imaging that can be used to deliver image-guided radiation 
therapy (IGRT). IGRT allows delivery of highly accurate, stereotactic radiation 
treatment. The use of cone beam CT images during IGRT is considered standard of 
care treatment. 
 
Uncertainties in tumor location are minimized because these machines have on-
board, volumetric imaging for accuracy in initial patient setup; kV and MV projection 
imaging during treatment is used to monitor delivery accuracy and/or make 
corrections to the patients’ position.  The radioactive tracer FDG will be used to 
perform PET scans (when available), a special imaging procedure. Positron emission 
tomography (PET) is a type of nuclear medicine examination, which is based on the 
administration of a small amount of a radioactive FDG agent. The tracer (FDG) is a 
modified form of glucose, a sugar normally found in the bloodstream and used by 
cells in the body for energy.  FDG is eliminated in the urine. With special imaging 
equipment, it is possible to detect radiation from the administered radioactive agent 
and obtain images of the body.  
 
6.2.5 
Risk Information 
It is difficult at this time to predict with confidence the percentage rate of 
complications from the proposed Linac based SBRT treatment. However, it is 
reasonable to extrapolate from the current experience with radiotherapy in and around 
the pancreas. Based upon prior phase I and phase II studies, we anticipate that the 
toxicities associated with this treatment will be acceptable. 
 
Toxicities commonly associated with such treatment include nausea, vomiting, 
fatigue, anorexia and weight loss. Severe side effects such as gastrointestinal (GI) 
obstruction, perforation, or hemorrhage are uncommon complications, occurring in 
<5% of patients undergoing standard radiation therapy for pancreatic cancer. 
Although we expect a comparable rate of complications with fractionated Linac 
based SBRT, it is important to note that vomiting, GI obstruction, GI hemorrhage, 
anorexia and weight loss are also commonly associated with pancreatic cancer 
progression.  Clinical and radiographic assessments will be performed in an effort to 
identify these effects, ascertain their etiology and provide the most appropriate 
palliative measures.  Hepatic and renal toxicity is not anticipated given the 
expectation of limited incidental irradiation of these organs. Complications, if any, 
will be graded according to the CTCAE, National Cancer Institute, version 4.0.  We 
will also utilize the RTOG scale for grading acute and chronic radiotherapy toxicities. 
 
6.3 
Duration of Study 
It is anticipated that this study will last approximately 42 months (30 months of accrual and 
12 months while cohort matures). 
6.4 
Duration of Follow Up 
We estimate that most patients will remain a subject in this study for approximately one year 
Patients will remain enrolled on this protocol for a maximum of 5 years or until patient 
withdrawal. One year after Linac based SBRT, patients should undergo standard follow-up 
every 3-6 months, as determined by the treating physician. Patients that have completed the 
5 year follow-up will continue being followed for survival information until death. The 
administration of subsequent chemotherapy and/or other antineoplastic treatment following 
Linac based SBRT will be at the discretion of each patient’s attending medical oncologist. 

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If participants become very ill and cannot travel to JHH for follow-up appointments, the study 
team will mail Quality of Life Questionnaires and requisition medical records from local 
providers. This is expected due to progression profile. If all protocol parameters are met this 
will not constitute a protocol deviation. 
 
6.5 
Criteria for Removal from Study 
Patients will be removed from the study for any of the following reasons: death or patient 
withdrawal.  The protocol director may also withdraw a patient from the study for one or 
more of the following reasons:  failure of the patient to follow the instructions of the protocol 
study staff, the protocol director decides that continuing participation could be harmful to the 
patient, pregnancy (if applicable), the patient needs treatment not allowed in the study, the 
study is cancelled, other administrative reasons, or unanticipated circumstances. Patients that 
have been removed from or discontinue the study will be followed for survival information 
until death. 
 
 
6.6 
Alternatives 
Alternative therapies include chemotherapy alone, standard chemotherapy/radiation, 
surgical re-exploration with possible re-resection, palliative symptomatic relief, or no 
further treatment.  Additionally, patients may choose to receive treatment to improve quality 
of life but that may have no effect on the growth of their cancer. The risks of chemotherapy 
and standard chemotherapy/radiation include nausea, vomiting, diarrhea, fatigue, bone 
marrow suppression, and sepsis.  The potential benefits of chemotherapy or standard 
chemotherapy/radiation are prolonged survival.  The risk of pursuing no further treatment is 
tumor progression or spread.  
6.7 
Compensation 
Subjects will not be paid to participate in the study. 
7.  ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS 
7.1 
Adverse Events and Potential Risks List 
Based upon our prior phase I and phase II studies evaluating the toxicities associated with 
Linac based SBRT for pancreatic cancer, we estimate that ≤20% of patients will experience 
grade 2 or higher late GI toxicity within one year.  Late GI toxicities are those events 
occurring more than 3 months after Linac based SBRT.  Acute GI toxicities are those events 
occurring within 3 months following Linac based SBRT.  The major toxicity in this group of 
patients is the development of duodenal/gastric ulcers.  Most of these are successfully 
managed medically.  However, Stanford has observed 2 cases of duodenal perforation 
associated with Linac based SBRT. We anticipate that because of refinements in radiation 
treatment planning techniques and because the dose will be divided over five treatments (as 
opposed to one), the biological equivalent and actual dose to the duodenum will be less than 
prior studies.  We anticipate that the risk of ulcer formation should be lower in this study.  
Hepatic and renal toxicity is not anticipated given the expectation of limited incidental 
irradiation of these organs and we have not observed any to date in the patients treated with 
Linac based SBRT.  Complications, if any, will be graded according to the RTOG 
Gastrointestinal Toxicity Scale and/or CTCAE v4.0. 
 

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7.2 
Reporting of Serious of Unexpected Adverse Events  
7.2.1  All fatal events, both anticipated and unanticipated, must be reported to the JHM 
IRB within a time period as specified by current institutional guidelines after the PI 
learns of the event, whether or not the PI believes the event to be related to the study. 
All other events, which are both serious and unanticipated, must be reported to the 
JHMI IRB within a time period as specified by current institutional guidelines after 
the PI learns of the event. Events which are serious but anticipated, should be 
reported as part of the continuing review application. If any of these Serious Adverse 
Events requires a change to the protocol or consent form, the PI must make those 
changes promptly and submit the revised documents to the JHM IRB. 
7.2.2 
Important Adverse Events that are unanticipated must be reported to the JHM IRB 
within a time period as specified by current institutional guidelines. If the Important 
Adverse Event requires changes to the protocol or consent form, the PI must make 
those changes promptly and submit the revised documents to the JHM IRB. 
7.2.3  All other unanticipated Adverse Events or changes to the protocol and consent form 
must be reported to the JHM IRB, within a time period as specified by current 
institutional guidelines  
 
Addendum (8/15/2014): 
Adverse events will be recorded using Mosaiq software, Low grade toxicities are to be 
expected given the disease profile. Any toxicity below CTCAE v4.0 grade 3 will not be 
reported on the Master AE Log or Case Report Forms. However, this information will be 
retained in patient charts.  
 
Towards end of life, hospitalization events increase within this patient population. 
Hospitalizations that occur greater than 30 days from completion of SBRT and that are not 
attributable to research intervention will be recorded on the Master AE Log and reported at 
the time of continuing review and SMC monitoring. 
 
These parameters are drafted in accordance with CFR21, though provide realistic 
expectations based on the sickness of this patient population. 
 
7.3  
Definitions  
Serious Adverse Event: means an event that is  
• fatal  
• life-threatening  
• persistent or significantly disabling or incapacitating  
• inpatient hospitalization or prolongation of hospitalization  
• congenital anomaly or defect and/or  
 
• a significant medical incident (considered to be a serious study  related event 
because, based upon appropriate medical judgment, it may jeopardize the subject 
and may require medical or surgical intervention to prevent one of the outcomes 
listed in this definition.)  
Important Adverse Event: means an event, although not a Serious Adverse Event, which still 
presents an undesirable occurrence that interferes with the subject’s usual activities and may 
be persistent or require treatment. (For example, serious rash, cough, or fever.)  
 
Unanticipated Adverse Event: means an event that results from a study intervention and was 
not expected or anticipated from prior experience. This includes expected events that occur 
with greater frequency or severity than predicted from prior experience.  

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8.  CORRELATIVE/SPECIAL STUDIES 
8.1 
Laboratory Correlative Studies 
8.1.1 
Analysis of patient plasma for biomarker development. 
8.1.1.1 Collection of Specimen(s) (optional): 
Patients will elect whether they want to participate in this portion of 
the study on the consent form. 
 
Blood Samples 
a) Blood (EDTA preserved) for research purposes will be drawn prior to 
radiation treatment (prefer before chemotherapy if possible) and at each 
follow-up along with the patient’s regular labs.  For each collection, up 
to 8 ml (1 large purple/violet tube or 2 small purple/violet tubes at 4 ml 
each) will be drawn. 
 
b) Within two hours from collection, blood will be centrifuged at 3000 
RPM for 10 minutes and plasma collected. The supernatent will be 
aliquotted for storage at -80°C into separate tubes.  The pellet will also 
be aliquotted and stored in separate tubes at -80°C. 
 
Tumor Biopsy Tissue Samples 
a) Consent for obtaining tumor samples:  All patients with a presumed 
diagnosis of pancreatic or periampullary cancer can give consent or 
decline consent to obtain additional tumor tissue for research purposes.  
In this situation, the research biopsy should be obtained only after a final 
diagnosis (preliminary if determined by the pathologist during the 
diagnostic biopsy) of pancreatic or periampullary adenocarcinoma has 
been reached by the pathologist. Once a preliminary/final diagnosis has 
been obtained, gold fiducials can be placed into the tumor for tumor 
tracking.  In the event the patient already has a confirmed pathologic 
diagnosis of pancreatic or periampullary cancer, a repeat endoscopic 
ultrasound, CT, or laparoscopic procedure may be used to place gold 
fiducials into the tumor for tumor tracking.  Following fiducial 
placement, additional tumor samples can be obtained for research 
purposes if the patient gives permission in the study consent. 
 
b) Tumor sample processing:  Fine needle aspirations (FNA) and core 
biopsies (if possible) of tumor tissue will be immediately placed into 
small cryovial tubes that can be stored at -80°C.  Sample tubes are 
immediately immersed into a canister of liquid nitrogen with 
forceps/tube holder until completely frozen.  Samples are then 
transferred into the -80°C freezer until utilization for biomarker analysis. 
 
8.1.1.2 Storage of Specimen(s) 
All samples will be stored at Johns Hopkins Hospital in Cancer Research 
Building II at -80°C or in liquid nitrogen until utilized for analysis of 
biomarkers.  
 
8.1.1.3 Site(s) Performing Correlative Studies 
All biomarker studies will be performed at Johns Hopkins Hospital by Dr. 
Narang or his staff or in the laboratory of a research collaborator. Specimen 

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samples will also be processed in the laboratories of Stanford Cancer 
Institute, Memorial Sloan Kettering Cancer Center, and Metabolon, Inc. 
 
We will utilize proximity ligation assay (PLA) to simultaneously interrogate 
a panel of 60-100 secreted proteins that we have developed for pancreatic 
cancer patients. PLA is an antibody based method of detection in which 
complementary single- stranded oligonucleotides are linked to each antibody 
pair.  When the 2 antibodies bind in close enough proximity, the local 
concentration increases, allowing for PCR amplification of this signal.  PLA 
is more sensitive than conventional ELISA and can be reliably multi-plexed 
for the detection of multiple protein panels (Fredrikkson et al).  In a pilot 
study, we have shown that when using this method of detection (Chang et 
al), we can accurately identify patients with pancreatic cancer.  In this study, 
we will expand the number of biomarkers and collect plasma at multiple time 
points during therapy.  The goal is to identify a biomarker panel that is 
predictive of patient outcome and/or response to therapy.  We hypothesize 
that not only is the pattern of secreted biomarkers important but the change 
in these biomarkers may be even more critical for prediction of clinical 
outcomes. 
 
8.1.1.4 Coding of specimens for privacy protection 
At the time of consent, each patient will be given a specific confidential 
identification number (IDN). Specimens will be stored under the patient’s 
IDN. The information can be shared with other investigators listed on this 
protocol. Study data will be maintained in password protected computer files 
(protected online database through Johns Hopkins). Only research personnel 
will have access to this information. 
8.2 
Collection of Pre and Post Treatment CT/PET Scans, Treatment 
Planning Scans, and Treatment Plans 
8.2.1 
Data and Image Collection 
8.2.1.1 Pre-Linac based SBRT PET scan is recommended but not required. Post -
SBRT PET scans will be optional for all patients based on the opinion of the 
treating physician. Pre- and post-Linac based SBRT CT scans will be 
mandatory for all patients (PET/CT may supplement protocol CT).  All 
images (CT and PET) will be stored electronically by JHU through the 
Oncospace network and be registered to each patient using the IDN. 
Radiation treatment plans will also be retrospectively reviewed and stored at 
JHU via Oncospace.  The JHU database is set up to store ROI geometries 
and dose distributions along with the CT.  This design facilitates the 
investigation of dosimetric effects on tumor response and complications 
utilizing DVH or other attributes of the 3D dose. 
 
For Pinnacle, the data can be directly placed in the JHU database via scripts.   
 
8.2.1.2 All treatment planning scans will be stored electronically by JHU through the 
Oncospace network and be registered to each patient using the IDN.  Specific 
parameters will be prospectively collected such as treatment volume and 
dose to adjacent structures in oncospace 
 
8.2.1.3  Dynamic Whole Body PET/CT 

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Up to 17 patients will be recruited to a sub-project that will assess the 
feasibility of acquiring a quantitative dynamic whole body PET/CT early 
after treatment. The aim of this sub-project is to assess the extent to which 
dynamic PET can be used to aid in the discrimination of tumor from 
radiation induced inflammation in a therapy assessment setting. This could 
potentially enable future PET/CT-based response assessment at an earlier 
time than the current protocol and clinical practice, 4-6 weeks post-
treatment.  This will allow therapy decision (success or failure) to be made 
earlier and management is personalized.  
 
Unlike conventional PET imaging, which performs single-pass multi-bed 
imaging of the subject, the proposed framework performs multiple-pass 
multi-bed imaging of the subject. The objective of this alternative imaging 
framework as developed and validated by Johns Hopkins Department of 
Nuclear Medicine, and implemented by major vendors, is to quantify the 
pattern of tracer uptake within the imaging duration, moving beyond 
conventional static imaging. This approach enables enhanced quantification 
of radiotracers uptake by tumors, and has the potential to enable improved 
differentiation of tumor recurrence from inflammation, and is hypothesized 
to arrive at improved assessment of therapy response and prediction of 
outcome. 
 
 In this sub-set of patients who consent to undergo this research imaging, two 
18F-FDG dynamic whole body PET/CT scans will be obtained using the 
novel protocol of dynamic whole body data acquisition.  Patients 
participating in this sub-project will have a PET/CT study performed in a 
dynamic whole-body mode at baseline and on day 5 of SBRT treatment.  
All PET/CT studies will be acquired on the Biograph mCT at the Johns 
Hopkins PET Center. Dynamic whole-body PET/CT scanning will last 
approximately 45 minutes, while single-pass whole-body PET/CT imaging 
last under 30 minutes, although the total duration of the patient visit is likely 
to be 2-3 hours. Each PET/CT study will involve intra-venous administration 
of 0.15 mCi / kg of 18F-FDG (maximum 17.5 mCi), similar to clinical FDG 
dose. Low-dose CT will be acquired at the same imaging session, similar to 
clinical protocol. The total effective dose for each PET/CT study is <0.4 rem 
for the CT and <1.2 rem for the PET. 
 
9.  
INVESTIGATOR RESOURCES 
9.1 
Qualifications 
The study staff will include, but is not limited to, the Principal Investigator, Co-Investigators, 
research coordinators, research nurses, and any residents or fellows working with the 
physicians.   
 
All study staff have completed the required training specific for their responsibilities in this 
study.  Furthermore, each member of the research team will be given a thorough explanation 
of the protocol and their responsibilities, including helping with scheduling, procedures, 
follow-up, data entry, or analysis.  All research investigators will be required to complete 
proper training through their institutional review boards. 

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9.2 
Use of Cancer Center Facilities 
Patients will be evaluated and treated in at Sidney Kimmel Cancer Center at Johns Hopkins 
Hospital.  All radiotherapy for this study will be performed in the department of Radiation 
Oncology at JHH.  Other procedures related to this study (i.e., blood draws, fiducial 
placement, imaging studies) will be carried out at JHH. 
9.3 
Conflict of interest 
There is no potential conflict of interest among the research personnel involved in this study. 
 

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10.   STUDY CALENDAR 
 
  
Pre-Study 
Pre-SBRT9 
SBRT Treatment10,11 
 
Follow-Up 6 
(Post-Radiation Treatment) 
4-6 
weeks 
4 mos 
64 
mos 
9 mos 
124 mos 
Yrs 2-5 Q 3-
6 mos 
Initial Consult 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
History / Physical Exam 
X 
 
X 
X 
X 
X 
X 
 
Informed consent 
X 
 
 
 
 
 
 
 
Biopsy  
(confirmed adenocarcinoma) 
X 
 
 
 
 
 
 
 
Labs: CBC, CMP, CA19-9 
 
X7 
X 
X 
X 
X 
X 
X 
Research Blood Sample (optional) 
 
X7 
X 
X 
X 
X 
X 
X 
Negative Pregnancy Test8 
 
X 
 
 
 
 
 
 
Seed Placement  
(EUS, CT, intraoperatively) 
 
X 
 
 
 
 
 
 
Research Biopsy  
(optional) 
 
X 
 
 
 
 
 
 
Simulation Scan 
 
X 
 
 
 
 
 
 
Radiologic Evaluation  
(CT1, PET-CT2) 
 
X 
X3 
X 
X 
X 
X 
X 
Dynamic Whole Body PET/CT 
 
X12 
X12 
 
 
 
 
 
 
Research dMRI 
 
X 
 
 
 
 
 
 
 
QoL  Questionnaire5 
 
X 
X 
X 
X 
X 
X 
X 
AE Evaluation13 
X 
 
X 
X 
X 
X 
X 
X 
1CT pancreas or chest/abdomen/pelvis, as per treating physician, required pre- and post-SBRT. However, may be supplemented by PET/CT (dual phase). 
2Pre-SBRT PET-CT scans and subsequent PET-CT scans are recommended but not required and may be ordered at the discretion of the treating physician.  
3If being reevaluated for resection, scans will be conducted at 4-6 weeks or as determined necessary by treating physician. 
4It is preferred that patients have the 6MFU and 12MFU evaluation and imaging at the treating institution.  Other evaluations may be done at a local center however records must be 
submitted to SBRT treating facility. 
5QoL questionnaires may be completed and returned by mail or email if preferred. 
6Follow-up appointments have a +/- 30 day tolerance window. (ex. 6MFU may occur between 5-7 months) 
7Pre-SBRT labs should be done within 4 weeks prior to treatment. 
8Pregnancy test by urine or serum, for women who are not post-menopausal as defined in Appendix III. 
9Pre-SBRT procedures should be completed within 45 days of beginning treatment. 
10It is recommended that patients in both cohorts discontinue any chemotherapy one week prior to SBRT and delay resumption of chemotherapy until one week following completion 
of SBRT 
11Ideally all 5 fractions should be delivered Monday through Friday; however, treatment may be delivered over 2 weeks, as long as the patient receives at least 2 fractions per week. 
 
12 Required if participant consents to PET scan research correlative. To be performed at baseline and Day 5 SBRT 
13Toxicity evaluation may be completed via telephone if participant cannot return for follow up. 

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11.  
MEASUREMENT OF EFFECT 
 
11.1 Anti-tumor Effect 
Patients will be evaluated for anti-tumor effect by follow-up imaging (pancreas protocol CT 
and/or PET-CT imaging) as outlined above. All subsequent scans (post-treatment) will be 
compared to the same pretreatment CT or PET/CT that was used in conjunction with radiation 
treatment planning. 
11.1.1 Definitions 
Patients will be evaluable for toxicity and evaluable for objective response at the 
follow-up intervals specified above. 
11.1.2 Disease Parameters 
 
Pancreatic and periampullary tumor response will be based upon standard 
radiographic criteria for the treated lesion and will be prospectively recorded in the 
JHU secure database. Radiographic response of the pancreatic or periampullary 
tumor by diagnostic CT scans will be defined according to RECIST criteria as 
described below: 
 
CR = complete disappearance of index lesion 
PR = at least 30% decrease in the longest diameter of the index lesion 
PD = more than 20% increase in the longest diameter of the index lesion 
SD = does not meet criteria for PR or PD 
 
Pancreatic or periampullary tumor response will also be assessed by FDG-PET scans 
(when available) according to the following criteria: 
 
CR = target lesion becomes photopenic or standardized uptake value (SUV) ratio of 
tumor/liver less than or equal to 1 
PR = decrease in SUV ratio of tumor/liver (at least 30%) PD = increase in SUV ratio 
of tumor/liver (at least 20%) 
SD = no significant change in SUV ratio of tumor/liver 
 
Local tumor progression will be defined as >=20% increased size on CT scan 
compared to a CT scan from prior to treatment. Distant progression will be defined 
as any new tumor found outside of the pancreas or periampullary region on CT scan.  
Local and/or distant progression by both PET  (if available) and CT scan will be 
recorded separately. We will also determine PET response with the new PERCIST 
criteria as reported by Wahl et al. (J Nuc Med 2009; 50:122S-150S). 
 
11.1.3 Methods for Evaluation of Measurable Disease 
Pancreas protocol CT scans (biphasic imaging, 1.25 mm cuts) and/or FDG PET-CT 
scans (optional and if recommended by the treating physician) will be obtained at all 
follow-up intervals as described in the treatment calendar. 
 
11.1.4 Response Criteria 
11.1.4.1 Evaluation of Target Lesions 
Patients’ responses to therapy will also be evaluated clinically after 
completion of their Linac based SBRT. The following are clinical 
definitions for response: 
 
CR = complete alleviation of pain or other symptoms thought to be related 
to the index lesion 

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PR = improvement, but not complete elimination, of pain or other symptoms 
thought to be related to the index lesion 
PD = worsening of pain or other symptoms thought to be related to the index lesion 
SD = does not meet criteria for PR or PD 
 
Radiographic response will be defined as outlined in section 11.1.2. 
 
11.1.4.2 Evaluation of Non-Target Lesions 
Standard radiographic criteria will be utilized for non-target lesions.  Any 
disease outside of the pancreas or periampullary region will be considered 
metastatic disease.  If possible a biopsy should be obtained to confirm 
metastasis. 
 
11.1.4. 3Evaluation of Best Overall Response 
This will be based upon the response of the treated lesion as described above. 
11.1.5 Duration of Response 
The criteria for overall response will be the time between treatment and first sign of 
local progression or development of new metastatic disease. 
 
11.1.6 Progression-Free Survival (or other parameters) 
The criteria for time to progression and progression-free survival (PFS) will be the 
duration from Linac based SBRT treatment to documented local/regional or distant 
progression or death.  Local PFS will be measured as the duration from Linac based 
SBRT treatment to local progression or death from any cause. 
 
11.1.7 Response Review 
All responses will be reviewed independently by a board certified radiologist at the 
study’s completion. Each image will be reviewed by the PI.  Simultaneous review of 
the patient’s chart will also occur at this time.  PET/CT images (if available as per 
the recommendation of the treating physician) and PERCIST measurements will be 
made by Jeff Leal and a staff member in the nuclear medicine department. 
12. 
DATA REPORTING / REGULATORY CONSIDERATIONS 
12.1 Monitoring Plan 
Johns Hopkins University will conduct yearly study audits to review subjects’ timely and 
complete enrollment, registration into the electronic database, and follow-up per study 
calendar.  More frequent monitoring will take place as needed. Trial monitoring with subject 
chart and trial binder reviews will be done by Johns Hopkins University per Sidney Kimmel 
Cancer Center guidelines. 
 
Subject data will be documented and stored in the electronic database Oncospace & Mosaiq, 
the software and infrastructure being supplied by JHH.   
 
12.1.1 Data Management 
This is a DSMP Level I study under the SKCCC Data Safety Monitoring Plan 
(9/22/2011). The Clinical Research Office QA Group will perform an audit after the 
first subject has been treated and then periodically depending on the rate of accrual 
and prior audit results. All trial monitoring and reporting will be reviewed annually 
by the SKCCC Safety Monitoring Committee. The PI is responsible for monitoring 
the study. Data must be reviewed to assure the validity of data, as well as, the safety 
of the subjects. The PI will also monitor the progress of the trial, review safety 

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reports, and clinical trial efficacy endpoints and to confirm that the safety outcomes 
favor continuation of the study. 
 
12.1.2 Data Entry and Compilation 
Research Staff (Coordinators, Nurse, or Co-Investigators) will enter/scan subject 
data into Oncospace, which will include: 
 
- 
Eligibility or Inclusion/Exclusion Criteria 
- 
Patient Demographics 
- 
Pre-Study Evaluation including H & P, Allergies, and Review of Systems 
- 
Surgical Procedures, with dates and findings (including EUS, biopsy (if 
needed), seed placement, and/or stent (if recommended) 
- 
Scan dates (PET/CT (if available) and/or CT) 
- 
Treatment planning date 
- 
Pre-Study Labs including hematology, chemistry, and tumor markers (CBC, 
CMP and CA 19-9) 
- 
Radiation therapy dates and toxicities reported 
- 
Follow-up Evaluations including H&P, Review of Systems, and toxicities 
- 
Follow-up labs and dates 
- 
Completion of QOL questionnaires 
- 
Subject study withdrawal, date, and reason 
- 
Concomitant medications, specifically PPIs and antiemetics, prescribed per 
protocol and if reportedly taken by subject 
 
Information will be entered from source documents or from Case Report Forms 
which are formatted to capture data as it will be entered into the database.  If 
information is entered from source documents directly into Oncospace, Case Report 
Forms can be printed out and signed or signed electronically. 
 
The PI will be responsible for maintaining the clinical protocol and subjects’ study 
charts, reporting adverse events, assuring that consent is obtained and documented, 
and reporting the status of the trial in continuing renewals submitted to their IRB and 
trail monitoring group(s) as per JHH protocol. 
 
There will be password-protected limited access to the database in order to maintain 
privacy (See Confidentiality below). 
12.2 Stopping Rules 
All outcome data (toxicity and efficacy) will be reviewed every 6 months by the Principal 
Investigator and key Co-Investigators.  This study will be monitored by the JHH IRB.  All 
potential adverse events will be reported to the SKCCC Data Safety Monitoring Committee 
and the JHH IRB.  An interim analysis is planned to assess late grade 2 or greater gastritis, 
enteritis, fistula, ulcer, or late grade 3 or greater GI toxicity when 16 patients are accrued. If 
7 or more patients have late grade 2 or greater gastritis, enteritis, fistula, ulcer, or late grade 
3 or greater GI toxicity within one year, the trial will be halted (note: accrual will continue 
while interim analysis is being conducted). After the first 16 patients are followed up for one 
year, we will also estimate the 1-year local progression free survival. If  the upper bound of 
a two-sided 98% confidence interval (alpha = 0.02) of local progression free survival is below 
30% in cohort A, or less than 50% in cohort B, the accrual at that cohort will be halted for 
lack of efficacy.  

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12.3 Confidentiality 
Study data will be maintained in password protected computer files.  Only research personnel 
listed on this protocol will have access to this information.  Only the patients unique IDN will 
be used.  The patient’s name or other public identifiers will not be included in any information 
shared with other investigators.  The study data with identifiers will be kept at Johns Hopkins 
under a separate confidential file. 
13.  
STATISTICAL CONSIDERATIONS 
13.1 Endpoints 
13.1.1 Primary Endpoint 
To evaluate late (>3 months after Linac based SBRT) grade 2 or greater gastritis, 
fistula, enteritis, or ulcer, or any other grade 3 or greater gastrointestinal toxicity 
attributable to fractionated Linac based SBRT.  
 
13.1.2 Secondary Endpoints 
- 
To determine rates of local progression free survival, overall survival, 
metastasis-free survival, and progression-free survival at 3, 6, and 12 months 
from Linac based SBRT.   
- 
To evaluate acute toxicity, defined as any grade 3 or greater gastrointestinal 
toxicity within 3 months of treatment.  
- 
To use FDG-(if available as per the recommendation by your treating 
physician) /CT scans for assessment of tumor response and progression. 
- 
To evaluate the role of FDG-PET scans in treatment planning. 
- 
To assess the quality of life before and after fractionated Linac based SBRT. 
- 
To further standardize Linac based SBRT delivery and dosimetric parameters. 
- 
To compare toxicity and outcomes among patients treated with fractionated 
Linac based SBRT delivered as 5 Gy x 5 (Cohort A of current protocol), 6.6 
Gy X 5 (Cohort B of current protocol), 25 Gy X 1 (previous study), and 5-
10 Gy x 3 (previous study). 
- 
To evaluate pain control ( as define by pain medication requirements at 3, 6, 
and 12 months following Linac based SBRT. 
 
13.2 Analysis Populations 
Efficacy analysis will be conducted on all patients who complete Linac based SBRT. 
 
13.3 Plan of Analysis 
Demographic and clinical characteristics of patients and the characteristics of treated lesions 
(volume, location, and modality) will be summarized by means, medians, standard deviations, 
ranges and proportions as applicable. Toxicities will be tabulated by type and grade at each 
follow-up interval. All adverse events will be reported to the SKCCC Data Safety Monitoring 
Committee and the JHH IRB.  The study may be stopped before reaching the accrual goal at 
the recommendation of any of these groups. The level of progression free survival (and other 
categorical outcomes) will be tabulated at each follow-up interval.  The percentage of 
individuals free from local progression will be computed with exact 95% confidence 
intervals.  Time to event outcomes (overall survival, metastasis free survival, and progression 
free survival) will be summarized using Kaplan-Meier curves and medians with 95% 

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confidence intervals calculated using Greenwood’s formula.  A competing risks analysis of 
local progression at 6, 12, and 18 months will be conducted.  The measurements of the volume 
of the pancreatic tumors based upon CT and/or PET-CT scans will be compared using paired 
t-tests or Wilcoxon signed-rank tests as appropriate. Quality of life at each interval will be 
calculated and compared using the recommended guidelines from the module (available by 
E-mail: c.d.johnson@soton.ac.uk). Vincent Bernard from MD Anderson will also help with 
data analysis. Data will be transferred via secure JH Box and totally anonymized. 
 
13.4 Sample Size 
13.4.1 Accrual Estimates 
This is a single institution, phase II study to evaluate the safety and efficacy of 
fractionated stereotactic body radiation therapy in subjects with unresectable or 
locally recurrent pancreatic or periampullary cancer. The study will recruit two 
cohorts of patients; one will be patients who had recurrent or residual disease after 
previous chemoradiation therapy (Cohort A), and the other will be patients who had 
recurrent or residual disease after surgery and/or chemotherapy without radiation 
(Cohort B). Cohort A will be treated with 5 Gy x 5 for palliative retreatment, and 
Cohort B will be given 6.6 Gy x 5 for definitive treatment. We anticipate recruiting 
2-3 patients per month for each cohort.  
13.4.2 Sample Size Justification 
The primary goal of this study is to access the late gastrointestinal toxicity rates 
including grade 2 or greater gastritis, fistula, or ulcer and any other grade 3 or greater 
gastrointestinal toxicity in Linac based SBRT patients. Two cohorts will be accrued 
in this study; one will be patients who recurrent or residual disease after previous 
chemoradiation therapy (Cohort A), and the other will be patients who had recurrent 
or residual disease after surgery and/or chemotherapy without radiation (Cohort B). 
Cohort A will be treated with 5 Gy x 5 for palliative retreatment, and Cohort B will 
be given 6.6 Gy x 5 for definitive treatment. Two cohorts will be evaluated 
separately.  
 
The sample size is 60 patients per cohort. The primary outcome used to determine 
the sample size is the percentage of individuals with a late gastrointestinal toxicity 
(grade 2-4) at one year. The late grade 2 or greater toxicity rates was previously 
observed for other treatment regiments for locally advanced pancreatic cancer were 
approximately 40% .We hypothesize that in each cohort, the toxicity rate for this 
regimen will be 20%, a 50% reduction. The stopping rules for futility were calculated 
based upon a two-stage design with a total sample size of 60 and an interim analysis 
of 16 patients (note: accrual will continue while interim analysis is being conducted). 
Within 16 patients, if 7 or more patients have late grade 2 or greater gastritis, enteritis, 
fistula, ulcer, or late grade 3 or greater GI toxicity, the trial will be stopped. If 6 or 
fewer patients have late grade 2 or greater gastritis, enteritis, fistula, ulcer, or late 
grade 3 or greater GI toxicity, then the study will continue enrolling patients until 60 
patients have been accrued. After 60 patients are enrolled, if 17 or more of the 
patients have late grade 2 or greater gastritis, enteritis, fistula, ulcer, or late grade 3 
or greater GI toxicity, the null hypothesis will not be rejected. If 16 or fewer of the 
patients have late grade 2 or greater gastritis, enteritis, fistula, ulcer, or late grade 3 
or greater GI toxicity, we will conclude that one year late toxicity is below 40%. This 
design will reach 91% power with 2% type I error for grade 2 or greater late toxicity, 
and the probability of early termination is 0.47. In addition, this sample size will 
reach 89% and 90% power to test the increase of 1-year local progression free 
survival from 30% to 45% in cohort A and 50% to 65% in cohort B, respectively. 

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The calculation is based on a one-sided test at significance level 0.04, assuming 
exponential distribution for local progression time and 2.5 year uniform accrual time 
with 1 year follow up.  
13.5 Interim Analyses for Efficacy 
After the first 16 patients are followed up for one year, we will estimate the 1-year local 
progression free survival. If  the upper bound of a two-sided 98% confidence interval (critical 
value alpha = 0.02) of  local progression free survival does not exceed 30% in cohort A, or 
less than 50% in cohort B, the accrual at that cohort will be halted and trial will be re-
evaluated. 
 
13.6  Data Analysis 
We will perform separate analyses for Cohorts A and B. Descriptive summary statistics 
(mean, median, standard deviation, range, or proportion) will be presented for demographic 
and clinical characteristics of patients or treated lesions. 
 
Toxicity will be summarized by type and grade for each cohort. The rate of grade 3 or higher 
GI toxicity will be estimated along with its 95% CI. This study will evaluate the efficacy of 
fractionated Linac based SBRT based on local-regional progression free survival (LFSP).   
LPFS is defined as the elapsed time from the start date of Linac based SBRT treatment to the 
date of documented local/regional tumor progression or death, whichever occurs first. We 
will plot the Kaplan-Meier curve for LPFS and estimate 1-yr local control and its 95% 
confidence interval based on KM estimate and Greenwood’s formula. In addition, we will 
consider death without local progression as a competing event, and estimate cumulative 
incidence rate of local-regional progression using a competing risk analysis.   
 
Other outcomes to be studied in this group of patients include, overall survival (OS), 
progression free survival (PFS) and quality of life. OS is defined as the elapsed time from the 
start date of Linac based SBRT treatment to death due to any cause; PFS is the time from the 
start date of Linac based SBRT treatment to disease progression or death, whichever occurs 
first. OS and PFS will be summarized using Kaplan-Meier plot.   
 
Quality of life will be assessed via EORTC QLQ-C30 (v3.0) questionnaires. Our study 
population is pancreatic cancer subjects, and the analysis will be focused on Global Health 
Status/QoL scale, symptom scale (fatigue, pain), and functional scale (physical functioning, 
role functioning, emotional functioning). For each module, summary statistics of the score 
will be reported as baseline and follow up time. Changes of quality of life score before and 
after treatment will be tested via paired t-test. In addition, mixture effect models will be fitted 
for accessing the quality of life changes over time. The frequency of patients who reach 
minimal clinically important difference of 10-points change from baseline will be tabulated 
by time. The time to definitive deterioration in quality of life will be analyzed using the 
Kaplan Meier method.  
 

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Appendix I 
 
EORTC QLQ-C30 

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

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