MMC 1

1 M.
Palta et al ASTRO RT for Pancreatic Cancer Guideline Practical Radiation Oncology
Practical Radiation Oncology (2019)
Radiation Therapy for Pancreatic Cancer: An

ASTRO Clinical Practice Guideline
Manisha Palta, MD,a* Devon Godfrey, PhD,a Karyn A. Goodman, MD,b

Sarah Hoffe, MD,c Laura A. Dawson, MD,d,e David Dessert,f William A.
Hall, MD,g Joseph M. Herman, MD, MS,h Alok A. Khorana, MD,i Nipun
Merchant, MD,j Arti Parekh, MD,k Caroline Patton, MA,l Joseph M.
Pepek, MD,m Joseph K. Salama, MD,a,n Richard Tuli, MD, PhD,o Albert
C. Koong, MD, PhDh
a. Duke University, Durham, North Carolina, Department of Radiation Oncology

b. University of Colorado Denver, Aurora, Colorado, Department of Radiation Oncology
c. Moffitt Cancer Center, Tampa, Florida, Department of Radiation Oncology
d. Princess Margaret Cancer Centre, Toronto, Ontario, Canada, Radiation Medicine Program
e. University of Toronto, Toronto, Ontario, Canada, Department of Radiation Oncology
f. Patient representative, Wylie, Texas
g. Medical College of Wisconsin, Milwaukee, Wisconsin, Department of Radiation Oncology
h. MD Anderson Cancer Center, Houston, Texas, Department of Radiation Oncology
i. Cleveland Clinic, Cleveland, Ohio, Department of Hematology and Medical Oncology
j. University of Miami, Miami, Florida, Division of Surgical Oncology
k. Banner MD Anderson Cancer Center, Phoenix, AZ, Department of Radiation Oncology
l. American Society for Radiation Oncology, Arlington, Virginia
m. Princeton Radiation Oncology, Princeton, New Jersey
n. Durham VA Medical Center, Durham, North Carolina, Department of Radiation Oncology
o. Memorial Sloan Kettering Cancer Center, New York, New York, Department of Radiation Oncology
*
Corresponding author: Manisha Palta, MD, Duke University, PO Box 3085, Durham, North Carolina 27710
Email address: manisha.palta@duke.edu
Task Force Members’ Disclosure Statements

Before initiating work on this guideline, all task force members completed disclosure statements and pertinent
disclosures are published within this report. Where potential conflicts were detected, remedial measures to
address them were taken.
Laura Dawson: Merck (advisory board [ended], research funding), Raysearch (licensing fees), Sirtex Medical
(advisory board, honoraria, travel expenses [all ended]), UpToDate (honoraria), miscellaneous speaking at
academic institutions and cancer societies (honoraria and travel expenses); David Dessert (Patient
representative): CSRA (travel expenses, consumer reviewer for government research grants [all ended]), Facing
1
2 M. Palta et al ASTRO RT for Pancreatic Cancer Guideline Practical Radiation Oncology
Our Risk of Cancer Empowered (FORCE) (travel expenses [ended]); Devon Godfrey: Advances in Medical Physics
(royalties), tomosynthesis imaging patents (no royalties currently earned); Karyn Goodman: AstraZeneca
(research funding), RenovoRx (advisory board, consultant); William Hall: Elekta, National Cancer Institute,
American Cancer Society (all research funding); Joseph Herman: AbbVie (consultant [ended]), Augmenix
(consultant), Boston Scientific (consultant), Bristol-Myers Squibb (advisory board, consultant), BTG (consultant),
Celgene (advisory board [ended], consultant [ended], research funding) , Galera Therapeutics (research funding),
Oncosil Medical (research funding); Sarah Hoffe: Applied Radiation Oncology (journal advisory board), IBA
(travel expenses [ended]), RefleXion Medical (honoraria [ended]), UptoDate (honoraria), Varian (educational
honoraria, research funding); Alok Khorana (American Society of Clinical Oncology representative):
AngioDynamics (consultant, honoraria [ended]), Array BioPharma (research funding), Bayer (consultant,
honoraria, and travel expenses), Bristol-Myers Squibb (research funding), Halozyme (consultant, honoraria),
Janssen (advisory board, honoraria, travel expenses), Leo Pharma (honoraria, consultant), Merck (research
funding), Parexel (honoraria, consultant [both ended]), Pfizer (honoraria [ended]), Pharmacyclics (honoraria,
consultant [both ended]), Phamacyte (honoraria, consultant [both ended]), Sanofi (honoraria, consultant [both
ended]), Seattle Genetics (consultant [ended]), TriSalus (honoraria, consultant [both ended]); Albert Koong (Co-
Chair): Aravive Inc. (stock); Manisha Palta (Co-Chair): Oakstone (honoraria [ended]), Merck (research funding),
Navigant (consultant [ended]); UptoDate (honoraria), Varian (research funding); Joseph Salama: Abbvie
(research funding); Richard Tuli: AstraZeneca (advisory board, research funding); Nipun Merchant (Society of
Surgical Oncology representative), Arti Parekh, Caroline Patton, and Joseph Pepek reported no disclosures.
Disclaimer and Adherence — ASTRO guidelines present scientific, health, and safety information and may
reflect scientific or medical opinion. They are available to ASTRO members and the public for educational and
informational purposes only. Commercial use of any content in this guideline without the prior written consent
of ASTRO is strictly prohibited.
Adherence to this guideline does not ensure successful treatment in every situation. This guideline should not be
deemed inclusive of all proper methods of care or exclusive of other methods reasonably directed to obtaining
the same results. The physician must make the ultimate judgment regarding any specific therapy considering all
circumstances presented by the patient. ASTRO assumes no liability for the information, conclusions, and
findings contained in its guidelines. This guideline cannot be assumed to apply to the use of these interventions
performed in the context of clinical trials. This guideline is based on information available at the time the task
force conducted its research and discussions on this topic. There may be new developments that are not
reflected in this guideline and that may, over time, be a basis for ASTRO to revisit and update the guideline.
Acknowledgements: The task force thanks the peer reviewers for their comments and time reviewing the
guideline. See Appendix 1 for their names and disclosures. They also acknowledge Shushan Rana, MD and Xiao
Zhao, MD for literature review assistance.
2
Table of Contents
Preamble .................................................................................................................................................... 3
1. Introduction ............................................................................................................................................ 5
2. Methods ................................................................................................................................................. 5
2.1. Task Force Composition............................................................................................................................... 5
2.2. Document Review and Approval ................................................................................................................. 6
2.3. Evidence Review .......................................................................................................................................... 6
2.4. Scope of the Guideline ................................................................................................................................ 6
3. Key Questions and Recommendations ..................................................................................................... 7
3.1. Key Question 1: Indications for conventionally fractionated RT or SBRT ................................................... 7
3.2. Key Question 2: Dose-fractionation and target volumes .......................................................................... 12
3.3. Key Question 3: Sequencing of chemotherapy and RT ............................................................................. 17
3.4. Key Question 4: Simulation considerations ............................................................................................... 18
3.5. Key Question 5: Treatment planning techniques ...................................................................................... 24
3.6. Key Question 6: Indications for palliative RT ............................................................................................. 26
3.7. Key Question 7: Prophylactic medications for toxicity .............................................................................. 27
4. Emerging Data/Future Directions ........................................................................................................... 30
5. Conclusion ............................................................................................................................................ 30
Figure 1. PRISMA Diagram ......................................................................................................................... 31
References................................................................................................................................................ 32
Appendix 1. Peer Reviewers and Disclosures (Comprehensive) ................................................................... 40
Appendix 2. Abbreviations ........................................................................................................................ 41
Appendix 3. Selected Studies Supporting Recommendations...................................................................... 42
Appendix 4. Literature Search Strategies ................................................................................................... 50
Preamble
As the leading organization in radiation oncology, the American Society for Radiation Oncology (ASTRO) is
dedicated to improving quality of care and patient outcomes. A cornerstone of this goal is the development and
dissemination of clinical practice guidelines based on systematic methods to evaluate and classify evidence,
combined with a focus on patient-centric care and shared decision-making. ASTRO develops and publishes
guidelines without commercial support, and members volunteer their time.
Disclosure Policy — ASTRO has detailed policies and procedures related to disclosure and management of
industry relationships to avoid actual, potential, or perceived conflicts of interest. All task force members are
required to disclose industry relationships and personal interests, from 12 months before initiation of the
writing effort. Disclosures go through a rigorous review process with final approval by ASTRO’s Conflict of
Interest Review Committee. For the purposes of full transparency, task force members’ comprehensive
disclosure information is included in this publication. The complete disclosure policy for Formal Papers is
available online.
3
Selection of Task Force Members — The Guideline Subcommittee strives to avoid bias by selecting a
multidisciplinary group of experts with variation in geographic region, gender, ethnicity, race, and areas of
expertise. Representatives from organizations and professional societies with related interests and expertise are
also invited to serve on the task force.
Methodology — The task force uses evidence-based methodologies to develop guideline recommendations in
accordance with the National Academy of Medicine (formerly Institute of Medicine) standards. The evidence
identified from key questions (KQs) is assessed using the Population, Intervention, Comparator, Outcome,
Timing, Setting (PICOTS) framework. A systematic review of the KQs is completed, which includes creation of
evidence tables, that summarize the evidence base task force members use to formulate recommendations.
Table 1 describes the recommendation grading system.
Consensus Development — Consensus is evaluated using a modified Delphi approach. Task force members
(except for the patient representative) confidentially indicate their level of agreement on each recommendation
based on a 5-point Likert scale, from “strongly agree” to “strongly disagree”. A pre-specified threshold of ≥75%
of raters that select “strongly agree” or “agree” indicates consensus is achieved. Recommendation(s) that do not
meet this threshold are removed or revised. Recommendations edited in response to task force or reviewer
comments are re-surveyed prior to submission of the document for approval.
Annual Evaluation/Updates — Guidelines are evaluated annually beginning 2 years after publication for new
potentially practice-changing studies that could result in a guideline update. In addition, the Guideline
Subcommittee will commission a replacement or re-affirmation within 5-years of publication.
Table 1. ASTRO recommendation grading classification system
Strength of Overall Quality of Recommendation

Definition
Recommendation Evidence Grade Wording
• Benefits clearly outweigh risks and burden, or risks and
Any “Recommend/
burden clearly outweigh benefits.
Strong (usually high or Should”
• All or almost all informed people would make the
moderate)
recommended choice for or against an intervention.
• Benefits are finely balanced with risks and burden or
appreciable uncertainty exists about the magnitude of
benefits and risks. Any “Conditionally
Conditional • Most informed people would choose the recommended (usually moderate Recommend”
course of action, but a substantial number would not. to very low)
• There is a strong role for patient preferences and
shared-decision making.
Overall Quality of
Definition
Evidence Grade
High We are very confident that the true effect lies close to that of the estimate of the effect
We are moderately confident in the effect estimate: The true effect is likely to be close to the
Moderate
estimate of the effect, but there is a possibility that it is substantially different
4
Our confidence in the effect estimate is limited: The true effect may be substantially different from
Low
the estimate.
We have very little confidence in the effect estimate: The true effect is likely to be substantially
Very Low
different from the estimate.
1. Introduction
In 2018, an estimated 55,440 new cases of pancreatic cancer were diagnosed in the United States, with
44,330 estimated deaths from the disease, making pancreatic cancer the fourth leading cause of cancer-related
death.1 Fewer than 20% of patients present with tumors amenable to resection and, even among patients with
localized disease, the 5-year overall survival (OS) is typically <25%.2 Historically, pancreatic cancer has been
associated with high rates of local recurrence, but this has been overshadowed by the high rates of distant
metastatic disease. Newer multidrug systemic therapy regimens have shown efficacy in the metastatic setting
and are now increasingly being incorporated into the locally advanced and localized settings. With
improvements in distant disease control, local control becomes increasingly important.
The role of radiation therapy (RT) in the treatment of pancreatic cancer is uncertain. For resected
pancreatic cancer, adjuvant therapy has been supported by the early Gastrointestinal Tumor Study Group
(GITSG) study, which demonstrated an OS and disease-free survival (DFS) benefit.3 However, subsequent
European studies did not demonstrate a benefit for chemoradiation4-8 and there has since been a continental
divide in adjuvant therapy. In the United States, adjuvant chemoradiation continues to be the subject of ongoing
debate, and the recently completed Radiation Therapy Oncology Group (RTOG) 0848 will serve to clarify this
question.
Technical advances in respiratory motion assessment, respiratory management, and treatment planning
and delivery have allowed for stereotactic body radiation therapy (SBRT), which has demonstrated promising
local control and quality of life with acceptable rates of toxicity.9,10 This RT modality is increasingly being utilized
and investigated for patients with locally advanced pancreatic cancer (LAPC) and borderline resectable
pancreatic cancer (BRPC).
Previous pancreatic cancer guidelines from the American Society of Clinical Oncology (ASCO) have
focused on the multidisciplinary management in the potentially curable, locally advanced and metastatic
settings.11-14 This ASTRO guideline systematically reviews the evidence for RT in pancreatic cancer and provides
recommendations for simulation, treatment planning, and management of RT associated toxicities. The task
force recommends multidisciplinary evaluation and engagement of patients in decision-making, taking into
account their individual values and preferences.
2. Methods
2.1. Task Force Composition
The task force consisted of a multidisciplinary team of radiation oncologists (ROs), a medical physicist, a
medical oncologist, a surgical oncologist, a radiation oncology resident, and a patient representative. The ROs
were drawn from academic institutions, community or private practice, and the Veterans Affairs system. This
5
guideline was developed in collaboration with the American Society of Clinical Oncology and the Society of
Surgical Oncology who provided representatives and peer reviewers.
2.2. Document Review and Approval

The guideline was reviewed by 14 official peer reviewers (see Appendix 1) and revised accordingly. The
modified guideline was posted on the ASTRO website for public comment in October and November 2018. The
final guideline was approved by the ASTRO Board of Directors in March 2019. It is endorsed by the European
Society for Radiotherapy & Oncology and supported by the Royal Australian and New Zealand College of
Radiologists.
2.3. Evidence Review

A systematic review was conducted of literature involving human subjects published in English and
indexed in MEDLINE (through PubMed) from May 1, 2007 to June 5, 2017. KQ1 through 6 evaluated patients
with pancreatic cancer treated with RT, with or without chemotherapy, and KQ7 focused on studies of
prophylactic medications for acute or late toxicities from RT, primarily for abdominal or pelvic cancers. Both
Medical Subject Headings (MeSH) terms and text words were utilized and terms common to all searches
included: pancreatic neoplasms[Mesh]; pancreatic cancer; pancreas cancer; pancreatic neoplasm; pancreas
neoplasm; radiotherapy[Mesh]; radiation; and radiotherapy. Additional terms specific to the KQs were also used
and hand searches supplemented the electronic searches. For KQ1 through 3 and KQ6, only studies of
conventional fractionation with ≥40 patients and studies of SBRT with ≥20 patients were included. For KQ4 and
5, studies with ≥10 patients with pancreatic cancer were accepted. No size restrictions were placed on studies
related to KQ7.
The evidence tables, included in an Online Data Supplement, and search protocol summarize the
evidence used by the task force to formulate recommendations. References selected and published in this
document are representative and not all-inclusive. The outcomes of interest are shown in Table 2 below. See
Figure 1 for the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) diagram, which
includes additional details on the literature searches and the selected studies.
2.4. Scope of the Guideline

This guideline covers only the subjects specified in the KQs. Outside the scope are many other important
questions that may be subjects of other guidelines, including recurrent disease, intraoperative RT,15 and critical
quality and safety considerations for SBRT in general, which are addressed in the ASTRO white paper on
stereotactic radiosurgery and SBRT.16
The guideline recommendations are based only on the published data during the literature review
period. However, new data presented while the guideline was in development are discussed in the Emerging
Data/Future Directions section.
6
Table 2. KQs in Population, Intervention, Comparator, Outcome (PICO) format
KQ Population Intervention Comparator Outcomes

1 Patients with pancreatic cancer Regimens that include Regimens that include • Survival
considered for adjuvant, conventionally SBRT • Tumor control
neoadjuvant, or definitive RT fractionated RT • Acute and late toxicity
2 Same as KQ1. Dose fractionation schemes and target volumes • Quality of life
for: (1) conventionally fractionated RT with
chemotherapy, (2) SBRT
3 Patients with pancreatic cancer Options for sequencing chemotherapy with RT
receiving RT
4 Same as KQ3. Motion management techniques, target • Target and normal tissue
surrogates for image guidance, and contrast delineation
administration options during CT simulation • Treatment planning technique
• Treatment delivery accuracy
• Dose to target and organs at risk
5 Same as KQ3. 3-D CRT IMRT or VMAT • Treatment delivery
• Dose to organs at risk
6 Patients with pancreatic cancer RT Chemoradiation • Survival
receiving palliative therapy • Tumor control
• Acute and late toxicity
• Quality of life
7 Patients with pancreatic cancer Prophylactic medications for toxicity Incidence and severity of acute and
receiving RT late toxicity
3-D CRT = 3-dimensional conformal radiation therapy; CT = computed tomography; IMRT = intensity-modulated radiation
therapy; RT = radiation therapy; SBRT = stereotactic radiation therapy; VMAT = volumetric-modulated arc therapy.
3. Key Questions and Recommendations

3.1. Key Question 1: Indications for conventionally fractionated RT or SBRT
In patients with pancreatic cancer, what are the appropriate indications for regimens that include
conventionally fractionated RT or SBRT as:
• Adjuvant therapy?
• Neoadjuvant therapy?
• Definitive therapy?
See Table E1 for the evidence supporting the recommendations.
7
Table 3. Recommendations for indications for conventionally fractionated RT or SBRT
Strength of Quality of
KQ1 Recommendations Consensus
Recommendation Evidence
1. Following surgical resection of pancreatic cancer, adjuvant
conventionally fractionated RT with chemotherapy in
select high-risk patients is conditionally recommended.
Conditional Low 92%*
Implementation Remark: High-risk clinical features would
include positive lymph nodes and margins regardless of tumor
location within the pancreas.
2. Following surgical resection of pancreatic cancer, adjuvant
SBRT is only recommended on a clinical trial or multi- Strong Very Low 100%*
institutional registry.
3. For patients with resectable pancreatic cancer,
neoadjuvant therapy is conditionally recommended.
4. For patients with borderline resectable pancreatic cancer
and select locally advanced pancreatic cancer appropriate
for downstaging prior to surgery, a neoadjuvant therapy
Conditional Moderate 85%*
regimen of systemic chemotherapy followed by
conventionally fractionated RT with chemotherapy is
conditionally recommended.
and select locally advanced pancreatic cancer appropriate
for downstaging prior to surgery, a neoadjuvant therapy Conditional Low 77%*
regimen of systemic chemotherapy followed by
multifraction SBRT is conditionally recommended.
6. For patients with locally advanced pancreatic cancer not
appropriate for downstaging to eventual surgery, a
definitive therapy regimen of systemic chemotherapy
followed by either (1) conventionally fractionated RT with Conditional Low 85%*
chemotherapy, (2) dose-escalated chemoradiation, or (3)
multifraction SBRT without chemotherapy is conditionally
recommended.
*
The medical physics representative abstained from rating these recommendations.
Adjuvant therapy
While surgery is considered the only potentially curative therapy for pancreatic cancer, outcomes are
limited by rates of local and distant recurrence that range from 50% to 90%.17,18 The rationale for adjuvant
therapy, therefore, is based on the high incidence of tumor recurrence. Adjuvant strategies include systemic
chemotherapy alone and with chemoradiation.
The role of adjuvant chemoradiation remains unclear. Historic studies of adjuvant chemoradiation,
including GITSG 9173,3 European Organization for Research and Treatment of Cancer,4 and European Study
8
Group for Pancreatic Cancer (ESPAC)-1,5,19 showed varying benefits to chemoradiation following surgery. These
trials have been criticized for their design and non-standard RT regimens.20 For adjuvant chemotherapy alone,
the results of the Charité Onkologie (CONKO)-001 trial showed an improved median survival of 22.8 months with
adjuvant gemcitabine compared with 20.2 months with surgical resection alone (P = .005),6,21 leading to
adoption of a chemotherapy alone approach using gemcitabine as an appropriate standard of care. Additional
data from the ESPAC-3 trial showed that gemcitabine has equivalent survival to 5-fluorouracil (5-FU) and
leucovorin with lower rates of grade 3-4 toxicity (7.5% versus 14%, P<0.01).22 More recently, results from the
ESPAC-4 trial compared gemcitabine and capecitabine versus adjuvant gemcitabine alone, reporting an
improved median overall survival with the combination (28.0 months versus 25.5 months, P = .032).8 A
chemotherapy alone approach has also been supported by a meta-analysis of data from 5 randomized
controlled trials (RCTs).23
Data to support phase III investigation of chemoradiation in the modern gemcitabine era are lacking
except for the RTOG 9704 trial, which did not have a chemotherapy alone arm but prospectively evaluated 5-FU-
based chemoradiation with either gemcitabine or 5-FU chemotherapy.24 Results showed worse outcomes in
patients with positive lymph nodes,25 a CA 19-9 ≥90 mg/mL after surgery,26 and RT delivery that did not adhere
to protocol guidelines.27 A subsequent analysis of RTOG 9704 showed chemoradiation in the setting of
pancreatic head tumors, a CA 19-9 <90 mg/mL, and RT that adhered to protocol guidelines was associated with
increased survival comparable to the CONKO-001 trial.28
Multiple single-institution series have also been published showing a benefit to adjuvant
chemoradiation. In a non-randomized prospective series of 271 patients at Johns Hopkins receiving adjuvant 5-
FU based chemoradiation, those who received adjuvant chemoradiation had improved median survival (21
months versus 14 months) compared to those undergoing surgical resection alone.29 A similar non-randomized
retrospective series from the Mayo Clinic showed superior median and 2-year OS for patients receiving adjuvant
chemoradiation (median: 25 versus 19 months; 2-year: 50% versus 39%), as well as a specific survival benefit in
those with involved lymph nodes and high-grade tumors.30 Combined data from the two institutions was
subsequently reported using a matched pair and propensity score analysis, showing that patients receiving
regimens incorporating adjuvant chemoradiation had improved survival in all subgroups.31
Further data to support the role of adjuvant chemoradiation has been reported in series with larger
numbers of patients.32 In a National Cancer Data Base (NCDB) population of 11,526 patients resected from 1998-
2002, patients treated with chemoradiation had superior survival compared to patients receiving chemotherapy
alone33 and Surveillance, Epidemiology, and End Results (SEER) reports34 showed similar findings with a superior
median and 5-year OS in those receiving adjuvant chemoradiation.
Another large multi-institutional study from the Central Pancreas Consortium evaluated 747 patients
from 7 high volume centers and showed a benefit for adjuvant chemoradiation in specific high-risk patients,
such as those with lymph node positive or margin positive disease.35 A subsequent study by the Central Pancreas
Consortium evaluated 1130 patients and found adjuvant chemotherapy had significantly fewer local recurrences
and distant recurrences, while adjuvant chemoradiation had significantly fewer local recurrences but not distant
recurrences. On subset multivariable analysis, adjuvant chemotherapy and adjuvant chemoradiation resulted in
fewer local recurrences in patients with lymph node positive and margin negative disease. No improvement in
local recurrence, distant recurrence, or OS was seen in patients with positive margins receiving either therapy.36
Data from a rapid autopsy series reported that up to 30% of patients with intact SMAD4 (DPC4) tumors
on immunohistochemistry die more often from locally destructive tumors with fewer metastases37 than patients
with mutant SMAD4, but there has not yet been prospective validation of this finding in the adjuvant setting to
9
potentially aid patient selection strategies. Moreover, there are few studies available to guide decision making
based on tumor location in the pancreas except for a SEER analysis suggesting outcomes are not significantly
different.38 Until further data become available, the literature supports a recommendation for adjuvant
chemoradiation based on individual risk evaluation, including lymph node and margin positivity, regardless of
tumor location within the pancreas. A patient-centered approach integrating the patient’s individual values and
preferences, such as desire for a maximally aggressive approach to treatment and tolerance for potential short
and long term toxicities of treatment in the setting of a local control but not survival benefit, should be used.
Until further data become available, the current literature supports a recommendation for adjuvant
chemotherapy alone following R0 surgical resection for node negative patients. However, in the setting of node
positive disease following R0 surgical resection and adjuvant systemic chemotherapy with no evidence of
disease recurrence on restaging, chemoradiation should be discussed, with a patient-centered approach
integrating the patient’s individual values and preferences, given the data supporting a local control benefit in
this context. At this time, although some retrospective studies suggest a local control benefit in the setting of
positive surgical margins (R1 resection), no prospective data support the benefit of adjuvant chemoradiation in
this setting. These conclusions are also consistent with the ASCO guideline for potentially curable pancreatic
cancer.12
Data suggesting a role for SBRT in the adjuvant setting to allow for a rapid initiation of systemic therapy
after RT is limited to a small institutional series.39 As it is still investigational and carries a risk of substantial
toxicity, adjuvant SBRT for resected pancreatic cancer is currently only recommended as part of a clinical trial or
multi-institutional registry.
Neoadjuvant therapy
Historically, upfront surgery has been the standard of care because there were no other effective
therapies.40 However, resectable pancreatic cancer has high rates of distant progression and single-institutional
data have shown the safety and feasibility of a multidisciplinary neoadjuvant approach.41,42 Large retrospective
series of patients treated neoadjuvantly with concurrent gemcitabine and RT over 2 weeks and 5-FU-based
chemoradiation over 6 weeks following systemic therapy indicated equivalent outcomes and low toxicity.41
Prospective data is limited to small trials, such as the phase II study of 86 patients reporting a median survival of
34 months for the patients who underwent surgery after neoadjuvant chemoradiation compared to 7 months
for those who did not (P<.001).43 Similarly, a prospective RCT comparing immediate surgery with neoadjuvant
chemoradiation followed by resection comprised only 73 patients due to accrual problems and showed no
significant benefit, resulting in a median survival of 18.9 months for surgery alone versus 25 months for the
patients treated according to the protocol (P = .79).44 However, given the small number of prospective series
and the conflicting results from available meta-analyses and systematic reviews, which have failed to show an
OS benefit when compared to resection followed by adjuvant therapy, the true benefit is unclear.45-47 Based on
the level of available evidence, the indications for considering anatomically resectable pancreas cancer patients
for preoperative therapy are controversial. While high volume centers with multidisciplinary review may choose
to offer preoperative therapy to all resectable patients as part of their institutional treatment pathway, there is
not enough high-level evidence to support this recommendation outside of a registry or a clinical trial.
Multiple classification systems limit comparisons of studies of patients with potentially resectable
pancreatic cancer.48 Within the spectrum of pancreatic cancers classified as BRPC have been cases so
designated by virtue of anatomic imaging criteria, as well as patients who are marginal for surgery due to their
medical status or who have indeterminate findings for metastatic disease on imaging. Many of the existing
10
studies thus include retrospective reports of heterogeneous patient populations with diverse treatment
approaches. The primary objective of chemoradiation with patients with BRPC is to facilitate a margin negative
(R0) resection, which prospective evidence indicates conventionally fractionated RT and chemotherapy
effectively enhances.49 One prospective European trial of 41 patients delivered 5000 cGy in 200 cGy fractions
along with 5-FU to patients deemed “potentially resectable,” reporting that 63% underwent surgery with
negative margins in 80.7% and a pathologic response in 50%.50 With respect to patients with non-metastatic
pancreatic cancer, prospective evidence supports inclusion of regimens that include long course
chemoradiation.
The indications for considering higher dose SBRT regimens instead of long course chemoradiation center
around smaller tumors, generally ≤6 cm, located ≥1 cm away from a gastrointestinal mucosal organ without any
evidence of frank tumor invasion and those that are not associated with any grossly positive nodal disease.51-54
These 2 techniques thus describe differing patient populations, which further complicates interpretation of their
reported outcomes. Despite the lack of prospective data, there are retrospective studies that support the safety
of neoadjuvant SBRT for patients with BRPC based on anatomic imaging emphasizing the R0 resection rates
>90% (See Appendix Table 1).55
In the FOLFIRINOX era, there are also published reports of patients with LAPC undergoing significant
downstaging after neoadjuvant chemotherapy such that eventual surgical resection is feasible. Designating such
patients accordingly at the initial multidisciplinary staging evaluation would have the advantage of tailoring a
neoadjuvant approach to facilitate potential future R0 resection. Retrospective data do support the safety and
feasibility of including SBRT in regimens of patients with LAPC and rates of eventual resection are 10% to 21%
for patients treated with induction FOLFIRINOX-based regimens. 55,56
Definitive therapy
For most patients with unresectable LAPC, eventual surgical resection will not be possible despite tumor
downstaging. The data for optimizing management of these patients is mixed. The prospective Locally Advanced
Pancreas (LAP)-07 international trial randomized patients with LAPC to chemotherapy alone or a conventionally
fractionated 5400 cGy RT regimen with 5-FU-based chemotherapy after 4 months of initial gemcitabine-based
systemic therapy. It found no difference in OS with the inclusion of chemoradiation. However, chemoradiation
was associated with improved local control and greater duration of time without needing cancer-related
treatment, suggesting an impact on quality of life.57
There are also data to support dose-escalated chemoradiation (doses above 5040 cGy) with concurrent
gemcitabine-based regimens.58,59 In one study, which used advanced radiation techniques that managed the
respiratory associated tumor motion and intensity-modulated radiation therapy (IMRT), dose-escalated
chemoradiation improved the 2-year freedom from local progression to 59% compared to 38% in historical
controls. When censoring for distant metastasis on multivariate analysis, achieving local control with
chemoradiation was shown to be an independent predictor of OS.60 Further, data from the Eastern Cooperative
Oncology Group (ECOG) 4201 phase III trial showed a 2-month survival advantage of chemoradiation with
concurrent gemcitabine versus gemcitabine alone. Although grade 3 or higher toxicity rates were similar
between the arms, there was more grade 4 toxicity (38% versus 6%) in the chemoradiation arm.61 In contrast,
the Fédération Francophone de Cancérologie Digestive and Société Française de Radiothérapie Oncologique
(FFCD-SFRO) trial that randomized patients to chemoradiation with 6000 cGy followed by gemcitabine or to
11
gemcitabine alone reported a worse OS (8.6 months) with the chemoradiation versus the gemcitabine alone (13
month, P = .03), with more grade 3-4 toxic effects.62
For definitive therapy, multifraction SBRT has been shown to be safe and effective in a multi-
institutional single-arm prospective trial with a 12.2% rate of grade ≥3 acute gastrointestinal toxicity and 8.5%
grade ≥3 late gastrointestinal toxicity.63 The 49 patients in this phase II trial received 1 cycle of gemcitabine
followed by 3300 cGy in 5 fractions followed by further gemcitabine with a reported median OS of 13.9 months.
Additional prospective data from single centers has also shown safety and efficacy.64-66 In a pooled analysis of 19
trials and 1009 patients with LAPC, SBRT appeared to be safe (<10% late gastrointestinal toxicity) and relatively
effective (73% local control at 1 year) for inoperable disease.10 However, no prospective studies have compared
conventionally fractionated RT to SBRT and therefore such studies are needed. Retrospective data from single-
institutional centers has reported the safety and efficacy of multifraction SBRT in this setting as well.55,56
3.2. Key Question 2: Dose-fractionation and target volumes

In patients with pancreatic cancer receiving RT, what are the appropriate dose-fractionation schemes and
target volumes for:
• Conventionally fractionated RT and chemotherapy?
• SBRT?
See Table E1 for the evidence supporting the recommendations. For details on motion management and image
guidance and their impact on appropriate margins, see KQ4.
Table 4. Recommendations for dose-fractionation and target volumes
1. For patients with resected pancreatic cancer selected for
adjuvant conventionally fractionated RT and
chemotherapy, 4500-5400 cGy in 180-200 cGy fractions Strong Moderate 85%*
with concurrent 5-FU-based chemotherapy is
recommended.
selected for neoadjuvant conventionally fractionated RT
and chemotherapy, 4500-5040 cGy in 180-200 cGy
fractions is conditionally recommended.
3. For patients with locally advanced pancreatic cancer
selected for definitive conventionally fractionated or
dose-escalated RT with chemotherapy, 5040-5600 cGy in
Conditional Low 100%†
175-220 cGy fractions with concurrent chemotherapy is
12
Implementation Remark: A number of fractionation schemes

are used for locally advanced disease; see Appendix Table 1
for a selection of the regimens tested in trials.
selected for SBRT, 3000-3300cGy in 600-660 cGy fractions
with a consideration for a simultaneous integrated boost Conditional Moderate 100%†
of up to 4000 cGy to the tumor vessel interface is
selected for SBRT, 3300-4000 cGy in 660-800 cGy Strong Moderate 100%†
fractions is recommended.
6. For patients with resected pancreatic head cancer
receiving adjuvant RT, use of the NRG Oncology
Strong Moderate 100%†
consensus panel guidance67 for clinical target volume
(CTV) delineation is recommended.
7. For patients with resected pancreatic body and tail
tumors receiving adjuvant RT, a CTV including the
pancreatic resection margin and regional nodal basins
Strong Moderate 100%†
indicated in the NRG Oncology consensus panel
guidance67 for pancreatic head lesions but excluding the
periportal/liver hilum nodal region is recommended.
selected for SBRT, a treatment volume including the gross
tumor volume (GTV) with a small margin is
recommended. Strong High 92%†
Implementation Remark: SBRT does not routinely treat

elective nodes.
selected for SBRT, a treatment volume including the GTV
with a small margin is recommended.
Strong High 100%†
Implementation Remark: SBRT does not routinely treat

elective nodes.
selected for definitive conventionally fractionated RT and
Conditional Moderate 83%†
chemotherapy, elective nodal treatment is conditionally
recommended.
*
†
The medical physics and surgical oncology representatives abstained from rating this recommendation.
13
Dose-fractionation
As discussed in KQ1, pooled retrospective data from Johns Hopkins29 and Mayo Clinic30 showing a
survival benefit with adjuvant chemoradiation form the rationale for postoperative RT with modern treatment
planning techniques and dose fractionation schemes. The task force recommendation reflects the protocol
utilized for RTOG 970424 and recently completed RTOG 0848,68 which also allows for the use of capecitabine.
In patients with BRPC, there are emerging data to support neoadjuvant RT for downstaging and
selecting patients to optimize R0 resection rates. MD Anderson has the largest historical prospective experience
and patients received either 5040 cGy in 180 cGy fractions or 3000 cGy in 300 cGy fractions with concurrent 5-
FU chemotherapy. These studies showed excellent rates of R0 resection (66% to 89% R0 rates) and favorable
survival outcomes (median OS 15-25 months) for those who were able to undergo surgery.43,69 A small,
multicenter single arm Alliance trial of pre-operative therapy for patients with BRPC built on these studies and
demonstrated high rates of surgical resection with negative margins using modified FOLFIRINOX followed by
chemoradiation to 5040 cGy.70 However, this study did not meet the inclusion criteria for this guideline as
results for only 22 patients were reported and therefore was not used to determine the recommendation. For
patients who are receiving concurrent chemotherapy for BRPC, capecitabine, infusional 5-FU, or gemcitabine are
possible chemotherapy regimens.
For LAPC, patients in the LAP-07 trial received 5400 cGy in 180 cGy fractions57 and a separate trial from
the Eastern Cooperative Oncology Group demonstrated a survival advantage for patients received concurrent
gemcitabine and RT to 5040 cGy in 180 cGy fractions versus gemcitabine alone.61 Both studies showed a benefit
in locoregional control with chemoradiation and were associated with acceptable toxicity profiles. Other
institutional studies have used various dose-fractionation schemes with concurrent chemotherapy with
comparable outcomes and toxicity and there are a number of acceptable fractionation and concurrent
chemotherapy regimens (Appendix Table 1). However, the task force suggests 5040-5600 cGy in 175-220 cGy
fractions for patients with LAPC receiving conventionally fractionated RT and chemotherapy based on
prospective and retrospective institutional data.58,71-73 As for patients with BRPC, either capecitabine, infusional
5-FU or gemcitabine are potential chemotherapy regimens to give concurrently with conventionally fractionated
RT.74
In addition, SBRT is an evolving and promising neoadjuvant therapy option for patients with BRPC. One
study from Moffitt Cancer Center showed encouraging rates of R0 resection (96% for those who underwent
curative intent surgery) with acceptable toxicity. In this study, patients were treated with 2500-3000 cGy in 5
fractions to the gross tumor volume with a median dose of 4000 cGy as a SIB to the region of vessel
abutment.55,75 The Alliance A021501 trial used 3300 cGy in 5 fractions, with up to 4000 cGy allowed as a
simultaneous boost to the tumor vessel interface.76 Based on these trials, the task force recommends 3000-4000
cGy in 5 fractions using SBRT in the neoadjuvant setting. Per the Alliance trial, the 4000 cGy volume should be
limited to the smaller volume at the tumor-vessel interface as a SIB.76
For patients with LAPC, SBRT has emerged as an alternative option for providing local control while
minimizing the duration of treatment and allowing rapid integration of aggressive systemic chemotherapy. Initial
studies examining single fraction RT showed promising rates of freedom from local progression and OS, but
rates of grade 3 or greater toxicity were high.77,78 Several small single-institution prospective hypofractionated
RT trials (ranging from 2-6 fractions), showed excellent rates of local control with acceptable toxicity (Appendix
Table 2). A phase II multi-institutional trial treated 49 patients with LAPC with 5-fraction SBRT sandwiched
between gemcitabine chemotherapy. Patients received up to 3 doses of gemcitabine followed by SBRT (3300
cGy in 660 cGy fractions), followed by additional gemcitabine. Freedom from local progression at 1 year was
14
78% and OS was 13.9 months. Grade 4 toxicity was seen in 2 patients and grade 5 (unrelated) toxicity in 3
patients.63
Retrospective data in the definitive setting suggests delivery of biologically effective dose ≥7000 cGy
results in improved locoregional control and OS compared to biologically effective dose <7000 cGy (17.8 months
versus 15.0 months, P = .03).51 Further investigation is ongoing to determine the optimal dose and fractionation
for SBRT.
Target volumes
In the past, treatment volumes included the tumor (intact) or tumor bed (resected) plus adjacent nodal
volumes. This resulted in large treatment volumes that limited the ability to deliver tumoricidal doses of RT and
prevented concurrent delivery of full dose systemic therapy due to increased toxicity.24 Recommended volumes
for adjuvant conventionally fractionated RT are outlined in the NRG Oncology consensus panel guidelines, where
the tumor bed plus adjacent lymph nodes are covered with 5040 cGy.67 For pancreatic body and tail cancers, the
CTV should include similar nodal volumes to pancreatic head tumors. The splenic hilar nodes should be removed
during splenectomy, so inclusion of the pre-operative location is at the judgement of the treating physician and
should be strongly considered in the presence of high-risk features, such as a positive margin, in the region of
the hilar nodes.
With intact tumors, questions arose regarding the need to cover all of the peri-pancreatic nodes and
research demonstrated nodal recurrences are rare when only the pancreatic tumor plus a small margin (0.5-1.5
cm) is used.58,79 A move to smaller margins allowed inclusion of full-dose chemotherapy49 and escalation of RT
doses above 5000 cGy.58,80 Advances in treatment planning techniques such as IMRT, volumetric-modulated arc
therapy (VMAT), and image-guided radiation therapy; use of fiducials; and motion management also facilitate
more accurate delivery of RT, which is discussed further in KQs 4 and 5. These sophisticated planning techniques
have permitted escalated doses of RT and avoidance of adjacent normal structures, resulting in decreased acute
and late adverse effects.81-83
Most dose-escalated approaches in the treatment of pancreatic cancer include coverage of only the
tumor plus a small margin (SBRT: 2-5 mm; IMRT: 5-20 mm). Still others incorporate dose painting or SIB plans
that deliver higher doses to the tumor (SBRT: 3300-5000 cGy; conventional RT: >5000 cGy). Systemic therapy
may address the subclinical nodal disease and thus reduce the need to cover larger nodal volumes. While
elective nodal coverage may be considered for conventional RT (4000-5000 cGy), it is not routinely
recommended for SBRT.
In the neoadjuvant setting for resectable, borderline resectable, and unresectable disease, most studies
of conventionally fractionated RT with chemotherapy treat tumor plus 0.5-2 cm CTV margins, often covering
specific nodal regions associated with peri-pancreatic vessels including the superior mesenteric artery, superior
mesenteric vein/portal vein, hepatic artery, and celiac axis. Other studies simply add a circumferential margin
around the tumor and do not specifically cover the nodal regions around the vessels. If treating with
neoadjuvant, conventionally-fractionated chemoradiation, creation of a CTV to include regional nodal basins can
be considered, which would be similar to postoperative pancreatic head and body nodal volumes. Standard
normal tissue dose constraints for conventionally fractionated RT (adjuvant or neoadjuvant) are shown in Table
5.
15
Table 5. Normal tissue dose constraints for conventionally fractionated RT
Structure RTOG 0848 QUANTEC

Spinal cord Max dose to a point that is 0.03 cc <4500 Max dose <5000 cGy
cGy
Liver Mean dose <2500 cGy Mean dose <3000-3200 cGy
Small bowel Max dose <5400 cGy V4500 cGy <195 cc
D15% <4500 cGy
Stomach Max dose <5400 cGy D100% <4500 cGy
D15% <4500 cGy
Bilateral kidneys Mean dose <1800 cGy Mean dose 1500-1800 cGy
D50% (if IMRT is utilized)
cGy = centigray; D15%/50%/100% = dose to 15%/50%/100% of the organ; V4500 cGy = volume receiving 4500 cGy.
With SBRT, a 2-5 mm GTV/internal target volume (ITV) to planning treatment volume expansion is used
to limit the dose to the stomach and bowel, particularly the duodenum, which is usually the dose limiting normal
structure. When incorporating dose escalation with SBRT or IMRT, a planning organ at risk volume (PRV) is used
to limit acute and late toxicity of adjacent small bowel and/or stomach. The PRV typically is a 2-5 mm expansion
on these organs at risk (OARs); this can lead to an underdosing of the GTV and/or planning treatment volume at
the interface of the OARs. In this context, the concept of simultaneous integrated protection was proposed to
quantify and limit underdosing.84,85 In addition to covering the tumor and lymph node regions, it is important to
deliver a high enough dose to the tumor-vessel interface, particularly the superior mesenteric vein, to increase
the likelihood of a R0 resection in patients with BRPC or LAPC who may undergo curative intent surgical
resection.86 Typical pancreatic SBRT normal tissue dose constraints are outlined in Table 6. Motion management
and daily image guidance are important for pancreatic SBRT and are discussed further in KQ4.
Table 6. Normal tissue dose constraints for SBRT
Structure Dose Constraints*

PTV V2000 cGy >95%
Organs at Risk
Spinal Cord V2000 cGy <1cc
Liver V1200 cGy <50%
Combined Kidneys V1200 cGy <75%
Duodenum V1500 cGy <9cc
V2000 cGy <3cc
V3300 cGy <1cc
Stomach V1500 cGy <9cc
V2000 cGy <3cc
V3300 cGy <1cc
Small Bowel V1500 cGy <9cc
16
V2000 cGy <3cc

V3300 cGy <1cc
Spleen No constraint
PTV = planning treatment volume; V1200/1500/2000/3300 cGy =
volume receiving V1200/1500/2000/3300 cGy.
*
Based on dose of 3300 cGy in 5 fractions (Herman et al63).
3.3. Key Question 3: Sequencing of chemotherapy and RT

In patients with pancreatic cancer receiving RT, what is the appropriate sequencing of chemotherapy with
RT as:
Table 7. Recommendations for sequencing of chemotherapy and RT in patients receiving RT
1. For patients with resected pancreatic cancer receiving
adjuvant therapy, delivery of chemoradiation following 4 Strong Moderate 92%*
to 6 months of systemic chemotherapy is recommended.
receiving neoadjuvant therapy, delivery of RT following 2 Strong Moderate 92%*
to 6 months of systemic chemotherapy is recommended.
3. For patients with unresectable or locally advanced
pancreatic cancer without systemic progression after 4 to
Strong Moderate 85%*
6+ months of chemotherapy, definitive RT is
recommended.
*
The type and duration of chemotherapy given with RT for pancreatic cancer depends on the clinical
stage and setting (neoadjuvant versus adjuvant) as well as performance status and comorbidities. Patients with
favorable performance status (ECOG 0-1) are typically offered FOLFIRINOX prior to RT. Patients who are elderly
or have a poor performance status (ECOG ≥2) are typically offered gemcitabine or gemcitabine and nab-
paclitaxel prior to RT. The duration of therapy (2-6+ months) depends on how patient tolerance and tumor
response (ie, no evidence of progression while on chemotherapy). Diarrhea, neuropathy, and hematologic are
common dose-limiting toxicities.
The CONKO-001 trial demonstrated significant improvements in disease-free and OS with the use of
postoperative gemcitabine as adjuvant chemotherapy versus observation in resected pancreatic
adenocarcinoma.7 The subsequent ESPAC-3 and ESPAC-4 trials established gemcitabine and, subsequently,
17
gemcitabine combined with capecitabine as common adjuvant therapy regimens.8,87 These data support the role
of adjuvant systemic therapy and thus that appropriate sequencing is systemic therapy followed by adjuvant
chemoradiation. The RTOG 0848 is evaluating the role of chemoradiation following 6 months of systemic
therapy in the adjuvant setting.68
Based on adjuvant studies, up to 20% of patients with resectable disease have undetected metastatic
disease at diagnosis and patients should receive RT (chemoradiation or SBRT) and/or resection after at least 2
months of chemotherapy to assist with patient selection for surgery. Various chemotherapy regimens have been
used in this setting including gemcitabine and 5-FU as well as combination therapies. Southwest Oncology Group
1505 is evaluating neoadjuvant gemcitabine and nab-paclitaxel versus FOLFIRINOX in patients who are
resectable (RT is only considered in the adjuvant setting for margin positive resections).88 The Moffitt and
Hopkins groups have demonstrated that chemotherapy followed by SBRT can be effectively delivered in the
borderline setting.56,89
The Alliance A021501 study is currently evaluating modified FOLFIRINOX with or without SBRT in
patients with BRPC.76 Some centers are also investigating upfront conventionally fractionated RT with
chemotherapy (5000 cGy) or SBRT alone (500-660 cGy times 5) without neoadjuvant chemotherapy, and this
may be considered in patients with contraindications to or a high risk of unacceptable toxicity from
chemotherapy. 75,90-92
If there is response or stable disease after 4-6+ months of induction chemotherapy, conventionally
fractionated RT with chemotherapy or SBRT provides an alternative to continuing chemotherapy alone. Further
chemotherapy may be given following chemoradiation or SBRT in selected patients. Alternatively,
chemoradiation or SBRT may be offered to patients who have received >6 months of chemotherapy but have
become intolerant to chemotherapy without progression.11 However, at this time, no RCTs looking specifically
at sequencing have been completed. If there is local disease progression following chemotherapy, but without
evidence of systemic spread, the prognosis is worse, and most would consider such patients palliative with no
chance for long term control. Chemoradiation or SBRT may be offered to patients who meet the following
criteria: (1) first line chemotherapy treatment is completed or terminated due to progression or toxicity; (2)
performance status of ECOG≤2; (3) a comorbidity profile that is adequate, including hepatic and renal function;
(4) no evidence of metastases; and (5) patient preference. In patients who do not meet the above criteria,
cannot tolerate chemotherapy and/or have metastatic disease, palliative RT may be offered for symptom
control.93
3.4. Key Question 4: Simulation considerations

In patients with pancreatic cancer receiving RT, how do the following impact target and normal tissue
delineation, treatment planning techniques, and treatment delivery accuracy for conventionally
fractionated RT and SBRT:
• Motion management?
• Image guidance?
• Contrast administration during computed tomography (CT) simulation?
18
Table 8. Recommendations for simulation consideration
1. For patients with pancreatic cancer receiving
conventionally fractionated pancreatic RT or SBRT
without breath-hold, a patient-specific respiratory motion
assessment (eg, 4-dimensional [4-D] CT simulation) is
Strong High 100%*
recommended.
Implementation Remark: For palliative or postoperative RT,

motion assessment and management may not be required.
2. For patients with pancreatic cancer receiving
conventionally fractionated RT for whom free-breathing
target motion is significant (>1 cm), a respiratory motion
reduction technique is conditionally recommended.
Implementation Remarks: Conditional Moderate 100%*

• For palliative or postoperative RT, motion assessment and
management may not be required.
• For respiratory motion management techniques, the end-
exhalation position may be more reproducible than
inhalation positions.
3. For patients with pancreatic cancer receiving SBRT, a
respiratory motion management technique is
recommended.
Implementation Remarks:
Strong High 100%*
• For palliative or postoperative RT, motion assessment and
management may not be required.
• For respiratory motion management techniques, the end-
exhalation position may be more reproducible than
inhalation positions.
4. For patients receiving conventionally fractionated RT for
pancreatic cancer, daily image guidance is recommended.
• Bony anatomy and surgical stents are each poor Strong Moderate 100%*
surrogates for pancreas target positioning; if used for
image guidance, large ITV margins are necessary.
• Where possible, cine (fluoroscopic) imaging is useful, in
addition to 2-dimensional or 3-dimensional image
19
guidance, to confirm that the ITV adequately accounts for

respiratory motion variations or intra-breath-hold drift.
5. For patients receiving SBRT for pancreatic cancer, daily
image guidance with fiducial markers and volumetric
imaging is recommended.
• Bony anatomy and surgical stents are each poor
surrogates for pancreas target positioning; if used for Strong Moderate 100%*
image guidance, large ITV margins are necessary.
• Where possible, the use of cine (fluoroscopic) imaging is
suggested, in addition to 2-dimensional or 3-dimensional
image guidance, to confirm that the ITV adequately
accounts for respiratory motion variations or intra-breath-
hold drift.
6. Unless there is a contraindication to IV contrast, patients
with pancreatic cancer treated with RT should receive IV
contrast at CT simulation; multiphasic CT with a high Strong High 100%*
contrast flow rate and injection volume and patient-
specific scan timing is recommended.
*
The surgical oncology representative abstained from rating these recommendations.
Motion management
Numerous studies have confirmed pancreatic motion in patients who are free-breathing is substantial
and highly variable. As summarized in Appendix Table 3, population-based estimates of mean pancreatic tumor
motion of up to 0.5 cm, 0.7 cm, and 2.0 cm, in the lateral (left-right = L-R), anteroposterior (A-P), and
craniocaudal (superior-inferior = S-I) directions, respectively, have been reported with no respiratory motion
management. However, the motion exhibited by an individual patient is often substantially different from the
population mean, so patient-specific 4-D motion estimates are generally presumed to be superior to population-
based estimates.
The impact of target motion on CTV and OAR dosimetry is complex and depends on several factors,
including: (1) magnitude of motion detected during simulation; (2) knowledge (or lack thereof) regarding the
respiratory phase of the CT for treatment planning; (3) reproducibility of simulated motion magnitude and its
mean position on a daily basis throughout treatment and during individual treatment sessions; and (4) type and
frequency of image-guidance employed during treatment. Interplay effects between tumor/OAR and multileaf
collimator motion may also impact the dose to the CTV/OAR for dose-modulated treatment delivery and are
generally more significant with increasing motion magnitude.
Per the International Commission on Radiation Units and Measurements Report 62, the CTV should be
expanded into an ITV to account for internal target deformation and motion. The ITV is intended to be large
enough to adequately address intra- and interfraction variability of the target motion and potential uncertainty
associated with any initial motion estimate, ideally derived from a 4-D CT motion-study. For critical OARs near
high dose regions (or near their tolerance doses), it may be advisable to expand OARs into PRVs that similarly
20
account for their motion and other positional uncertainties to reduce the risk of normal tissue complications, as
described in Section 3.2.3.94
Appendix Table 4 lists published population-based estimates of the margin expansions that may be
required to account for free-breathing pancreatic tumor motion, if patient-specific 4-D imaging data is
unavailable. These range from 0.6-1.2 cm (L-R), 0.5-1.5 cm (A-P), and 1.0-2.8 cm (S-I), when nothing is known
about an individual patient’s motion range or the respiratory phase of their treatment planning CT. In general,
smaller ITV expansions are possible when the respiratory phase of the treatment planning CT is known, while
larger cumulative expansions may be necessary when it is not. Campbell et al found margin expansions of just
0.3 cm (L-R), 0.4 cm (A-P) and 0.7 cm (S-I) were sufficient to account for 95% of intrafraction target motion when
the mean CTV position was known at simulation and daily treatment.95 Likewise, Feng et al reported treatment
planning from the end-expiration phase enabled margins to be preferentially applied in the direction of
expected motion (inferior and anterior), with smaller margins in the superior and posterior directions.96 In the
worst case scenario, where the respiratory phase of the treatment planning CT is unknown and target motion
information is similarly unavailable from on-treatment imaging (eg, if only non-fluoroscopic radiographic
imaging is employed), ITV margins encompassing the entire range of motion may need to be applied
symmetrically to ensure adequate CTV coverage, effectively doubling the overall target volume expansion.
The use of a patient-specific reference motion study, such as 4-D CT simulation, to assess ITV margins is
supported by data showing the variation in motion across patients exceeds the interfractional variation
observed in individual patients.97 However, data suggests the respiratory motion of individual patients varies
substantially during treatment, even in single sessions. In a study of 18 patients with pancreatic cancer, the
authors concluded “…the respiratory-induced motion of pancreatic tumors measured with 4-D CT was often not
representative for the tumor motion during treatment…” after finding significant differences in each direction in
the motion magnitudes measured on a 4-D CT reference session versus daily on-treatment cone beam
computed tomography projections in the majority of patients.98 While the differences were always <0.5 cm in
the L-R and A-P directions, 17% of cone beam computed tomography scans revealed motion differences in the S-
I dimension of at least 0.5 cm, and 36% differed by at least 0.3 cm (5% and 6% of cone beam computed
tomography scans differed by at least 0.3 cm in the L-R and A-P directions, respectively).
Likewise, Minn et al reported that, during treatment, pancreatic tumor motion exceeded predicted
tumor motion (by 4-D CT) >10% of the time in 80% (16/20) of the patients.99 Similarly, Knybel et al found
pancreatic tumor motion during treatment is only modestly predictable in the S-I direction from reference
measurements, and is not well predicted in the L-R or A-P dimensions. Furthermore, for ITVs created from a
reference session, 30% of patients in their study would have experienced an underdosage risk zone >0.3 cm due
to intra- and interfraction respiratory motion variability during treatment, and the motion amplitude was overall
found to vary intrafractionally with a coefficient of variation (standard deviation/mean) >25% in 25% of patients.
Thus, care must be taken to ensure that the ITV expansion adequately accounts for motion variance and
uncertainty associated with any motion estimate.
Respiratory motion management techniques that minimize the apparent target motion during beam
delivery, and typically therefore also reduce its variability, often decrease ITV margins. For the pancreas,
effective approaches include abdominal compression, and monitored breath-hold or respiratory gated RT.
Respiratory motion management is recommended for pancreatic SBRT and suggested for conventionally
fractionated pancreatic RT when free-breathing motion is significant.
Abdominal compression deforms abdominal anatomy and may reduce the distance between critical
OARs and the target volume, yet evidence suggests it is effective at reducing pancreatic respiratory motion. In a
21
study of 19 patients with pancreatic cancer with abdominal compression and a subset of 11 patients who also
received imaging without compression, Campbell et al reported mean tumor motion in the L-R/A-P/S-I directions
of 0.5/0.5/0.9 cm with compression versus 0.5/0.7/1.4 cm without, leading to reduced ITV margins in the A-P
and S-I dimensions.
Several groups have reported substantial motion and margin reduction by gating RT around either the
end-expiration or end inhalation respiratory phases, as illustrated in Appendix Tables 5 and 6. In the same set of
19 patients with pancreatic cancer, gating with a 40% duty cycle around the end-expiration phase further
reduced mean tumor motion to 0.3/0.4/0.6 cm in the L-R/A-P/S-I dimensions, allowing ITV margin expansions of
just 0.2 cm in each of the left, right, anterior, and posterior directions, and 0.3 cm superiorly and inferiorly, to
encompass 95% of the target motion.95 Likewise, Huguet reported gating under the same conditions reduced
mean motion in the L-R/A-P/S-I dimensions from 0.3/0.6/1.3 cm to 0.3/0.2/0.5 cm, enabling margins to be
reduced by approximately 50%.100
Data also exists to support minimizing motion by delivering pancreatic RT using a carefully monitored
breath-hold technique in properly selected patients, as illustrated in Appendix Tables 7 and 8. End-exhalation
breath-hold levels, in particular, have been shown to be quite reproducible, especially within a single
session.101,102 Patient breath-holds may be forced, controlled by an external spirometer and shut-off valve, or
voluntary, in combination with surface or internal marker (eg, fiducial) monitoring. Voluntary breath-holding
without dedicated equipment designed to monitor the breath-hold level is not recommended, due to
suboptimal reproducibility.
For both breath-hold and gating techniques, the end-exhalation position is believed to be more
reproducible than inhalation positions, especially across multiple fractions, because exhalation represents the
relaxed equilibrium state of the diaphragm, whereas inhalation requires muscle contraction, which is more likely
to vary over time. This is supported by Shiinoki et al, who found gating around the end-expiration position was
superior to gating around end inhalation, enabling smaller margins,103 as illustrated in Appendix Tables 5 and 6.
Heerkens et al also reported the end-expiration position was more reproducible for simulated gating than the
end inhalation position, and furthermore tumors spent more time during the respiratory cycle near the end-
expiration position than the end inhalation position, resulting in less motion for the same duty cycle.104 Lens et
al similarly found fiducial marker positioning was substantially more reproducible and motion following a
breath-hold was smaller at end-expiration than at end inhalation.98,105
Image Guidance
Daily image guidance with fiducial markers concurrent with volumetric imaging of regional soft tissues is
considered ideal, as this combined approach allows direct alignment of tissues in the immediate vicinity of the
tumor and the visualization of critical OARs. Future improvements in volumetric imaging may mitigate the need
for fiducial markers, but currently the 2 techniques are typically complementary. Fiducial markers are clearly
visible and unambiguous, which reduces daily alignment variability and enables motion assessment via highly
time-resolved imaging techniques such as 2-dimensional fluoroscopy. Many volumetric imaging technologies are
impacted by motion artifacts and volume averaging that potentially result in alignment variability, but they
provide important 3-dimensional renderings of soft tissues in and near the target and enable confirmation that
fiducial markers have not migrated.
Numerous studies have shown that registration to either surgical stents106 or bony anatomy does not
achieve results comparable to fiducial markers with volumetric imaging, necessitating larger margins, as
summarized in Appendix Table 9.
22
The dosimetric impact of aligning to bone or stents without increased margin expansions has been
examined. Pepin et al found alignment to a stent reduced the V90% coverage of the planning target volume
(PTV) by 11% on average in patients treated with end-exhalation gated IMRT plans of 5400 cGy in 30 fractions,
with PTV expansions of 0.5 cm. It also increased dose to the duodenum, bowel, and stomach over the maximum
tolerance in 3, 3, and 5 of 9 patients, respectively.107 Similarly, in a study of 7 pancreatic and 4 liver patients,
bony alignment resulted in a 46% probability that the GTV would not be fully covered when the target volume
was created according to the expansion PTV=ITV+0.3 cm.108
If alignment to bony anatomy or stents is employed, large ITV-to-PTV margins are required to ensure the
target is reliably covered. This is generally unacceptable in the setting of pancreatic SBRT, due to the resulting
high doses that would be delivered to critical normal structures, but may be satisfactory for conventionally
fractionated pancreatic RT.
Contrast Administration During CT Simulation

The high conformity and tight margins associated with OAR-sparing IMRT and VMAT plans make
accurate pancreatic target delineation critical, especially for SBRT. Unfortunately, in the absence of IV contrast,
pancreatic ductal adenocarcinomas typically have a density similar to the surrounding normal parenchyma in CT
simulation images and are therefore very subtle. Differences in the perfusion characteristics between tumor and
pancreas can be exploited in contrast-enhanced computed tomography (CECT) to substantially improve
pancreatic ductal adenocarcinoma conspicuity.
CECT simulation of the pancreas has traditionally been performed according to generalized abdominal
CT protocols, which yield results superior to non-contrast CT, but are not specifically optimized to maximizing
pancreatic tumor visibility. The simulation CT can be fused with diagnostic images that better show the tumor,
but this is frequently suboptimal due to differences in patient positioning, respiration status, and anatomic
deformation between the two image sets. Specialized diagnostic pancreatic CT protocols, which are now
standard, employ higher contrast flow rates (at least 4 mL/sec, and ideally ≥5 mL/sec, with an appropriately
sized IV catheter), total contrast volume (eg, 175 mL of contrast containing 300 mg/mL iodine), and scan timing
that is carefully tailored to capture the pancreas in specific contrast phases, triggered on a patient-specific basis
via bolus tracking or bolus testing methods. A large body of evidence in the diagnostic radiology literature from
the past 2 decades supports the described specialized pancreas- and patient-specific multiphase CECT scanning
protocols for improved pancreatic ductal adenocarcinoma visibility, which has become the diagnostic standard
for pancreatic ductal adenocarcinoma detection.
Consensus guidelines issued by the Society of Abdominal Radiology and the American Pancreatic
Association specifically recommend a dual-phase contrast CT protocol, including the pancreatic parenchymal
phase (PPP) and portal venous phase (PVP), for patients in whom pancreatic ductal adenocarcinoma is
suspected, and note that a single phase contrast CT is not sufficient for the assessment of the local tumor
extent.109 In addition to providing optimal lesion conspicuity, they note that the PPP enables the evaluation of
peripancreatic arteries, while the PVP enables evaluation of the portal venous system, which may be necessary
for visualizing the presence of vascular invasion. These guidelines are supported by numerous studies reporting
the apparent density difference between a pancreatic ductal adenocarcinoma and the pancreas is greatest in
the PPP and PVP contrast phases, with some enhanced conspicuity potentially present in the early arterial
phase. A small illustrative sample of these data is presented in Appendix Table 10.
Only limited quantitative evidence is available regarding the impact of single phase CECT or specialized
multiphase CECT on the pancreatic ductal adenocarcinoma GTV delineation task. Existing published data does
23
suggest tumor visibility is enhanced, and contouring confidence is improved, by contrast. Target volumes drawn
across multiple contrast phases differ, indicating unique information is indeed likely extracted from each scan.
In a study of GTVs drawn by 3 ROs on non-contrast 4-D CT and single-phase 3-D CECT and 4-D CECT data
from 10 patients with pancreatic ductal adenocarcinoma, Choi et al found that either CECT approach increased
the Hounsfield unit difference and contrast-to-noise ratio between tumor and normal pancreas, improved the
physician scoring of lesion visibility and regional vessel definition, and reduced the GTV volume and
interobserver variability.110
Meanwhile, in a study of 10 biopsy-proven patients with pancreatic ductal adenocarcinoma, Godfrey et
al evaluated lesion conspicuity and the consistency of SBRT GTVs drawn on different phases of triphase CECT
simulation scans acquired according to a diagnostic pancreas CT protocol. Two ROs consistently ranked the PPP
and PVP scans as qualitatively superior for the GTV definition task. However, GTVs contoured on each of the
phases were highly variable. The overlap ratios (Jaccard Indices) of GTVs drawn by a single RO on just the PPP
and PVP data ranged from 0.43 to 0.91, with a mean of 0.65, reflecting the unique perfusion information
extracted from each contrast phase. Furthermore, the symmetric 3-dimensional volume expansions necessary
for the PPP GTV to encompass the PVP GTV, and vice versa, ranged from 0.1 to 1.3 cm and 0.3 to 1.4 cm,
respectively, with mean values of 0.5 cm and 0.8 cm.111 The authors note that these differences were more
severe than, but generally consistent with, similar studies of the GTV contouring consistency in triphasic CT
scans of patients with hepatocellular carcinoma.112
In summary, contrast should always be administered for CT scans used for pancreatic GTV delineation,
unless contraindicated or the tumor can be adequately visualized without contrast. The scan timing of single-
phase CECT should be selected to coincide with the PPP or PVP. Multiphasic diagnostic CT protocols including
the PPP and PVP are preferred and are recommended for pancreatic SBRT.
3.5. Key Question 5: Treatment planning techniques

In patients with pancreatic cancer receiving RT, how do different treatment planning techniques (3-D
conformal radiation therapy [3-D CRT], IMRT, VMAT) impact treatment delivery and dose to OARs?
See Table E2 for the evidence supporting the recommendation.
Table 9. Recommendation for treatment planning
KQ5 Recommendation Consensus
1. For treatment of localized pancreatic cancer, modulated
treatment techniques such as IMRT and VMAT for
Strong Moderate 100%*
planning and delivery of both conventionally fractionated
and hypofractionated RT are recommended.
*
The medical physics and surgical oncology representatives abstained from rating this recommendation.
When delivering RT to pancreatic tumors, the choice of treatment planning technique has the potential
to impact treatment delivery and radiation exposure of nearby organs. One possible benefit of modulated
treatment techniques, delivered using either static fields or VMAT, compared to 3-D CRT is reducing dose to
24
surrounding normal tissues while ensuring conformal coverage of target volumes. Additionally, highly conformal
techniques allow for the possibility of increased dose to tumor volumes, both in conventionally fractionated and
hypofractionated/SBRT approaches. The potential disadvantages compared to 3-D CRT include increased dose
heterogeneity to tumor volumes, higher integral dose to non-tumor tissues, increased cost, and possibly longer
treatment times. There have been no prospective trials comparing modulated techniques versus 3-D CRT in the
treatment of patients with pancreatic adenocarcinoma, and most published studies comparing such techniques
have utilized dosimetric endpoints with limited toxicity and clinical outcomes data.
When considering the optimal treatment technique for pancreatic cancer, radiation dose to the kidneys,
liver, duodenum, stomach, small bowel and spinal cord is of concern. Identification and appropriate delineation
of these OARs for patients with pancreatic adenocarcinoma should be performed using all available imaging
data. In particular, careful attention should be paid to right kidney dose, since the majority of pancreatic tumors
originate in the head of the pancreas. Various methods to assess for renal function include kidney size/atrophy,
contrast clearance and delay, renal scan, etc. When concern for renal compromise exists, laboratory studies and
potentially a nuclear medicine renal scan should be performed to better understand the pre-RT renal
physiology.
The vast majority of studies comparing 3-D CRT to modulated techniques with regard to tumor
conformality and normal tissue exposure incorporated elective nodal irradiation of para-aortic, celiac axis,
superior mesenteric, and porta-hepatic lymph node basins (resected, borderline resectable, locally advanced
unresectable), as well the anastomoses (gastrojejunostomy, hepaticojejunostomy, pancreaticojejunostomy). For
more detail on recommended treatment volumes, see KQ2. Therefore, more contemporary studies comparing
modulated techniques to 3-D CRT demonstrate further reduction in normal tissue exposure simply due to the
exclusion of elective nodal basins from target volumes.
Target delineation in the era of 3-D CRT without contemporary image-guided radiation therapy
techniques has typically involved larger CTV/PTV margins and elective coverage of lymph nodes, as noted above.
Given larger treatment volumes in combination with inferior conformality, dose delivery to primary tumor rarely
exceeded 5000 cGy, as this remains the tolerance of many surrounding normal tissues. The increased
conformality provided by IMRT combined with a trend to forego elective nodal irradiation has led to
investigation of primary tumor dose escalation and ability to perform SIBs.
Most113 but not all114 analyses report modulated techniques reduce dose to normal tissues and ensure
more conformal coverage of targets compared to 3-D CRT. Specifically, most analyses have demonstrated
modulated techniques lowered dose to the kidneys, liver, duodenum, small bowel, and stomach.113 However,
most studies do not demonstrate reduced dose to spinal cord, likely due to acceptance of a higher spinal cord
dose to achieve a reduction in dose to other OARs subject to clinically significant acute or late toxicities (small
bowel, stomach, liver, kidneys). Additionally, modulated techniques have improved target conformality.114
When compared to static field IMRT, VMAT plans demonstrate improved target coverage and reduced doses to
normal tissues.115,116 Typically in these comparisons, the specific organs spared depend significantly on location
of and proximity to primary tumor targets and a priori planning goals that vary vastly from study to study.
RT delivery time is an important concern particularly when using sophisticated techniques such as
breath hold or delivering high dose per fraction therapies such as SBRT. Simpler 4-field unmodulated RT plans
are typically the fastest to deliver, while static field IMRT plans, usually requiring more independent gantry
positions to achieve superior conformality, take longer to deliver. VMAT dose delivery commonly takes
significantly less time than static field IMRT and closely approximates 3-D CRT plans in most,113,117 but not all,118
studies.
25
While technical advancements related to the use of intensity modulation in the treatment of pancreatic
cancer have resulted in reduced dose to normal tissues when compared to 3-D CRT, clinical data on associated
improvement of acute and sub-acute gastrointestinal toxicities is limited. Some studies have reported lower but
not statistically significant rates of anorexia, nausea, and emesis with modulated techniques compared to 3-D
CRT. 117,119 Retrospective data suggests equivalent clinical outcomes between patients treated with IMRT and 3-
D CRT, indicating the more conformal treatments are likely not compromising treatment efficacy.81
For SBRT, reduction in acute side effects compared to conventionally fractionated RT is postulated by
excluding surrounding normal tissues as much as possible from clinical target volumes. In turn, this requires a
high degree of tumor conformality, accuracy, and verification of treatment delivery. As a result, SBRT is most
commonly delivered using modulated techniques. Retrospective data comparing SBRT delivered using 3-D CRT,
IMRT or via robotic radiosurgery in patients with resectable pancreatic cancer identified lower mean and
maximum dose to renal vessels with 3-D CRT, but improved mean and maximum dose to liver and superior
mesenteric artery and improved conformity index with IMRT-SBRT. Clinical data have not demonstrated
improvements in acute or late toxicities based on differences in planning techniques for SBRT, as most patients
are treated with modulated techniques given the data demonstrating improved normal organ sparing with these
approaches.
Therefore, the task force recommends IMRT/VMAT treatment planning techniques, given greater
conformality, lower dose to OARs, potential reduction in acute and late toxicities and equivalent clinical
outcomes.
3.6. Key Question 6: Indications for palliative RT

In patients with metastatic pancreatic cancer, what are the appropriate indications for RT in palliative
therapy?
See Table E1 for the evidence supporting the recommendation.
Table 10. Recommendation for palliative RT
KQ6 Recommendation Consensus
1. For selected patients with metastatic pancreatic cancer,
palliative RT to either the primary or select metastatic Strong Moderate 100%*
sites for symptom management is recommended.
*
The medical physics representative abstained from rating this recommendation.
Palliative treatment refers to relief of a tumor-related symptom. This discussion is limited to patients
who have clinical concern or evidence of metastatic disease, for whom there are few existing data on RT or
chemoradiation. For treatment of the primary disease site, a few retrospective, nonrandomized studies have
evaluated the role of RT in patients with stage IV disease.120 In one study of 24 patients, 64% had metastatic
disease and 80% reported significant pain prior to treatment. Post-RT, 50% of patients achieved pain control and
no longer required analgesics, while another 15% noted reduction in dose of pain medications. This was
achieved with no observed grade ≥3 toxicity.121 In a second study of RT in 71 patients, 8 patients had metastatic
26
disease and 81% of all patients experienced symptomatic relief of local symptoms.122 In an additional study, 63
patients, 50% with metastatic disease, were treated with IMRT and 50% also received concurrent
chemotherapy. All 44 patients experiencing abdominal/back pain prior to treatment reported improvement
after RT or chemoradiation.123 These cohort studies indicate high rates of local symptomatic relief are achieved
with RT alone. However, the level of evidence to support this recommendation is moderate given reliance on
small, retrospective series. For patients with symptoms warranting palliation to the pancreas primary,
reasonable palliative regimens could include 2000 cGy in 5 fractions or 3000 cGy in 10 fractions. In the rare
situation of bone metastases, 800 cGy in 1 fraction, 2000 cGy in 5 fractions, or 3000 cGy in 10 fractions can be
used, consistent with the ASTRO guideline on this topic.124 The extent of metastatic disease burden and
performance status of the patient should be considered in determining the optimal palliative RT regimen.
3.7. Key Question 7: Prophylactic medications for toxicity

In patients with pancreatic cancer receiving RT, how do prophylactic medications impact the incidence and
severity of acute and late toxicities?
Table 11. Recommendations for prophylactic medications for toxicity
1. For patients with pancreatic cancer undergoing RT,
prophylactic use of anti-emetic medications to reduce the Strong Low 100%*
rate of nausea is recommended.
2. For patients with pancreatic cancer undergoing RT,
prophylactic use of medications to reduce acid is Conditional Very Low 100%*
*
One task force member was recused from voting on this KQ based on disclosures.
The mitigation of acute and late toxicities is an important aspect of the management of patients treated
with RT for pancreatic adenocarcinoma. Treatment with conventionally fractionated RT and chemotherapy or
with SBRT can be associated with both acute and late toxicities at rates as high as 20% to 40%.57,63 The mitigation
of these toxicities needs to be carefully considered by ROs. With the goal of preventing both acute and late
toxicities, ROs frequently prescribe preventive or prophylactic medications. However, some ROs use a “rescue”
strategy of prescribing such medications only upon the development of symptoms, despite evidence that
prophylactic administration is beneficial. 125,126 However, while prophylactic medications can improve symptoms,
these medications can also have potential acute and late toxicities. Therefore, ROs should individualize
prophylactic medical interventions. Many of the RCTs evaluating this question have not focused on pancreatic
patients specifically and have included multiple abdominal or pelvic malignancies. This makes the data
important, but not always directly applicable to patients with pancreatic adenocarcinoma.
The overwhelming majority of data on symptom mitigation centers on preventing nausea. A
considerable number of RCTs over the past decades evaluated prophylactic anti-nausea medications in patients
27
being treated with RT. These trials have been the subject of 2 meta-analyses for abdominal/pelvic
malignancies126 and for a range of malignancies.127 The majority of trials in these meta-analysis addressed the
prophylactic addition of 5-hydroxytryptamine-3 receptor (5-HT3) antagonists to treatment with concurrent
chemoradiation. The results of these meta-analyses show a benefit of 5-HT3 receptor antagonists (such as
ondansetron) over other agents.
This data supports the routine and prophylactic use of 5-HT3 receptor antagonists in patients at risk for
RT induced nausea. However, there are no RCTs that specifically address this question in patients with
pancreatic adenocarcinoma and the published clinical trials have included a heterogeneous group of patients,
with a range of malignancies and treated with a variety of RT fractionation schedules.
There are several alternative anti-emetics to 5-HT3 receptor antagonists, such as neurokinin-1 (NK-1)
receptor inhibitors, and data directly evaluating the benefits of such alternative anti-emetics is limited. A RCT
enrolled 40 patients with abdomino/pelvic malignancies and randomly assigned these patients to receive either
ondansetron (a 5-HT3 receptor antagonists) alone, as compared with ondansetron and aprepitant, a NK-1
receptor inhibitor.128 Patients treated with aprepitant and ondansetron as compared with ondansetron alone
had a statistically significant improvement in RT-induced nausea. However, there are substantial limitations to
this data that make its routine clinical adoption unlikely. Such limitations included a small and highly
heterogeneous group of patients and treatment with a variety of management strategies. It is difficult to know if
the same type of improvements would be seen in patients with only pancreatic adenocarcinoma. A non-
randomized trial also came to conflicting conclusions. In this single arm trial, the effectiveness, safety, and
tolerability of dual NK1-receptor and 5-HT3 was assessed. The conclusion of this series was that aprepitant and
ondansetron concurrently were not superior to standard ondansetron.129
A high-quality RCT represents one of the largest studies to address routine use of prophylactic NK-1
receptor inhibitors in patients being treated with concurrent chemotherapy and RT. Despite this trial’s strength,
the population was limited to patients with cervical cancer, which makes its applicability to pancreatic cancer
unclear. In this trial, patients were randomly assigned to fosaprepitant (prodrug of the NK-1 receptor antagonist
aprepitant) versus placebo. Those receiving prophylactic fosaprepitant had lower rates of RT induced nausea
compared with placebo.130 Despite its indirectness, this trial supports the benefit of prophylactic medical
intervention, although the advantage of NK-1 receptor antagonists over 5-HT3 receptor antagonists in
pancreatic adenocarcinoma remains unclear.
Interestingly, there is limited data to either support or refute the routine use of medications to either
neutralize or suppress the production of gastric acid during RT, despite their frequent use by ROs. It is also worth
considering the potential impact on the absorption of oral chemotherapy medication with the use of acid
suppression.131 The use of such medications should be carefully considered secondary to potential effects on the
absorption of oral chemotherapeutic agents.
Given the paucity of publications directly evaluating this KQ in patients with pancreatic adenocarcinoma,
we conducted a survey of the physician members of the task force to better understand how they use
prophylactic medications in this population. Results of the survey can be seen in Table 12. It is clear that most
members of the task force recommend and prescribe antacids or proton pump inhibitors for patients
undergoing both SBRT and concurrent chemoradiation. Interestingly, only 7 out of 12 respondents routinely
prescribe anti-emetic medications for patients undergoing concurrent chemoradiation alone. When providers
did prescribe anti-emetic medications, the majority used one medication and favored ondansetron. Similarly, all
providers who prescribed antacid medications used either omeprazole or pantoprazole. Additional research into
28
the benefits of prophylactic interventions in patients with pancreatic adenocarcinoma is needed especially for
interventions outside of techniques to mitigate nausea and vomiting.
Table 12. Results from survey of task force practice patterns for prophylactic medications (KQ7)
Survey Question Yes No

Do you routinely prescribe or recommend an antacid or PPI medication for
patients undergoing treatment with concurrent chemoradiation for pancreatic 10 2
adenocarcinoma?
Do you routinely prescribe or recommend an antacid or PPI medication for
9 3
patients undergoing treatment with SBRT for pancreatic adenocarcinoma?
Do you routinely prescribe anti-emetic medications prophylactically for patients
undergoing treatment with concurrent chemoradiation for pancreatic 7 5
adenocarcinoma?
Do you routinely prescribe anti-emetic medications prophylactically for patients
9 3
undergoing treatment with SBRT for pancreatic adenocarcinoma?
Do you routinely recommend vaccines for patients with distal pancreatic tumors
2 10
with radiation exposure to the spleen?
PPI = proton pump inhibitor; SBRT = stereotactic body radiation therapy.
N = 12
For interventions to mitigate late toxicity, there is also a paucity of data that suggests the need for
further study. Patients with pancreatic tail lesions may have a substantial amount of RT exposure to the spleen
and, given that RT can theoretically cause changes in the function of lymphatic tissue there is a risk of splenic
dysfunction following radiation exposure. While limited evidence exists regarding the role for vaccination
following RT exposure to the spleen, this is something ROs may need to consider. Specific immunizations that
may be used are those against encapsulated bacterial pathogens, which are thought to potentially decrease the
rate of postsplenectomy sepsis. Such vaccinations are similar to those patients undergoing splenectomy and
include pneumococcal, meningococcal, and Haemophilus Influenza.132 Further, a publication by Trip et al
examined splenic RT doses carefully in patients undergoing RT for gastric cancer. They concluded the spleen
often received a high dose of radiation, which was associated with a reduction of the volume of the spleen.
Given that pneumonia and fatal sepsis occurred frequently following treatment for gastric cancer, this was felt
to be potentially attributed to functional hyposplenia.133 Additional research is needed into radiation dose to the
spleen and infectious complications following treatment with RT and the role for vaccinations following splenic
radiation exposure remains uncertain.
Finally, digestive malabsorption is a potential side effect following both surgery and RT in patients with
pancreatic adenocarcinoma. Careful follow up and consideration by oncologists to include medications to
mitigate malabsorption are important to consider, however detailed recommendations were considered to be
outside the scope of this guideline.
29
4. Emerging Data/Future Directions

A number of pancreatic cancer clinical trials are ongoing or recently completed. These trials seek to
clarify indications for RT for this malignancy and may alter currently presented recommendations or the quality
of evidence supporting recommendations.
There are few completed prospective studies to define the role of neoadjuvant SBRT for borderline
resectable pancreatic cancer. The ALLIANCE trial (NCT 02839343) was designed to randomize patients
randomized to either modified 5-FU, leucovorin, irinotecan, oxaliplatin (FOLFIRINOX) times 8 cycles alone prior
to surgical resection or 7 cycles of modified FOLFIRINOX plus SBRT consisting of 3300 cGy in 5 fractions to
evaluate the primary endpoint of OS at 18 months. Patients also receive adjuvant leucovorin, fluorouracil, and
oxaliplatin.76 The SBRT arm of the study was recently closed to accrual and we await the trial results from the
investigators. With recent retrospective data for patients with locally advanced disease showing improved local
control with higher biologically effective dose, future prospective dose escalation studies are needed.134,135
The Unicancer GI PRODIGE 24/CCTGPA.6 trial is a recently published multicenter phase III study of
adjuvant gemcitabine or modified FOLFIRINOX. Between 2012 and 2016, 493 patients were enrolled on this
multicenter study. An improvement in disease-free survival, metastasis-free survival, and OS with the use of
adjuvant modified FOLFIRINOX. With median follow up of 33.6 months, the median OS with adjuvant
gemcitabine was 35 months compared to 54.4 months in modified FOLFIRINOX arm.136 These data are likely to
alter the adjuvant therapy landscape and Radiation Therapy Oncology Group 0848 will have to be interpreted
with these results in mind.
At the 2018 American Society of Clinical Oncology Annual Meeting, a number of abstracts were
presented that could impact the management of pancreatic cancer in the coming years. In the area of
neoadjuvant treatment, the preoperative chemoradiation versus immediate surgery for resectable and
borderline resectable disease trial (PREOPANC-1) will provide the first prospective, phase III data for this patient
subgroup. At the time of presentation, 246 patients were accrued between 2013-2017 and randomized to
immediate surgery or preoperative chemoradiation. The preoperative regimen consisted of 3600 cGy in 15
fraction with concurrent gemcitabine 1000 mg/m2. For the primary endpoint of OS, median OS was 17.1 months
in the chemoradiation arm compared to 13.5 months.137
While this list is not intended to be comprehensive; these trials are likely to influence future versions of
the ASTRO pancreatic cancer guideline.
5. Conclusion
The role of radiation in the management of pancreatic cancer is evolving in the adjuvant, neoadjuvant,
and definitive settings, as is the use of SBRT, with advances in motion management, target delineation,
treatment planning, and image guidance. Such techniques have furthered dose escalation and ablative RT with
improved local control and quality of life and acceptable toxicity. RT is likely to become even more important as
new systemic therapies are developed and there is increased focus on controlling local disease. The appropriate
role and integration of SBRT with systemic therapy and surgery is an ongoing area of active investigation. It is
important that the nuances of available data are discussed with patients and families and that care for patients
with pancreatic cancer be coordinated in a multidisciplinary fashion.
30
Figure 1. PRISMA Diagram

Identification
Records identified through Additional records identified

database searching through other sources
N = 709 N = 26
Records after duplicates removed

N = 735
Screening
Abstracts excluded
N = 446
Abstracts screened Preclinical data: N = 50
N = 735 Excluded article/study type:
N= 70
Out of scope: N = 326
Other: N = 4
Abstracts excluded
Eligibility
Abstracts assessed for

N = 91
eligibility by task force
Out of scope: N = 27
N = 270
Too few patients: N = 64
Studies abstracted in
Included
evidence tables
N = 179
PRISMA = Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Created based on Moher D, Liberati A, Tetzlaff J, and Altman DG, 2009.138
31
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159. McNulty NJ, Francis IR, Platt JF, Cohan RH, Korobkin M, Gebremariam A. Multi-detector row helical CT of the
pancreas: effect of contrast-enhanced multiphasic imaging on enhancement of the pancreas, peripancreatic
vasculature, and pancreatic adenocarcinoma. Radiology. 2001;220(1):97-102.
160. Scialpi M, Cagini L, Pierotti L, et al. Detection of small (</= 2 cm) pancreatic adenocarcinoma and surrounding
parenchyma: correlations between enhancement patterns at triphasic MDCT and histologic features. BMC
Gastroenterol. 2014;14:16.
39
Appendix 1. Peer Reviewers and Disclosures (Comprehensive)

Disclosure Company/
Name Employment Disclosure Type
Organization
Edgar Ben-Josef, MD* University of Pennsylvania None
- Vice-Chair for Translational Research
- Professor of Radiation Oncology
Thomas Brunner, MD‡ University of Magdeburg – Director of None
Radiation Therapy Clinic
Daniel Chang, MD* Stanford University – Professor of Radiation Varian Research funding
Oncology Viewray Stock
Clifford Cho, MD† University of Michigan Department of Veterans Research funding
- Division Chief of Hepatopancreatobiliary Affairs
and Advanced Gastrointestinal Surgery
- Professor of Surgery
Michael Haddock, MD* Mayo Clinic – Consultant, Department of None
Radiation Oncology
Florence Huguet, MD, Assistance Publique Hôpitaux de Paris and Merck Serono Board member
PhD* Université Paris Sorbonne – Radiation Merck Sharp & Dohme║
oncologist Bristol-Myers Squibb
AstraZeneca
Harvey Mamon, MD, - Brigham and Women’s Hospital – Clinical UptoDate Honoraria
PhD* Director, Radiation Oncology
- Dana-Farber Cancer Institute – Chief,
Division of Gastrointestinal Radiation
Oncology
- Harvard Medical School – Associate
Professor of Radiation Oncology
Andrew Oar, MBBS, Liverpool Cancer Therapy Centre – None
MIPH§ Radiation Oncologist
Alexander Parikh, MD, Greenville Health System Genentech Speakers bureau
MPH† - Medical Director of Hepatobiliary,
Pancreatic, and GI Surgical Oncology
- Clinical Professor of Surgery
William Regine, MD* University of Maryland School of Medicine None
– Professor and Chair of the Department of
Radiation Oncology
Manish Shah, MD¶ New York Presbyterian – Attending Merck Research grants
Physician
Joel Tepper, MD* University of North Carolina School of ASCO Honoraria
Medicine – Professor of Radiation Oncology
Vincenzo Valentini, MD‡ Università Cattolica S. Cuore, Gemelli ART – None
Director of Department of Diagnostic
Imaging, Radiation Oncology, and
Hematology
Christopher Willett, MD* Duke University – Professor and Chairman Entrinisc Health Solutions Advisory board
of Radiation Oncology
*
American Society for Radiation Oncology reviewer; † Society of Surgical Oncology reviewer; ‡ European Society for
Radiotherapy & Oncology reviewer; § Royal Australian and New Zealand College of Radiologists reviewer; ║relationship
ended 12/15/2017; ¶ American Society of Clinical Oncology reviewer
40
Appendix 2. Abbreviations
3-D CRT = three-dimensional conformal radiation therapy
4-D = 4-dimensional
5-FU = 5-fluorouracil
5-HT3 = 5-hydroxytryptamine-3 receptor
A-P = anteroposterior
BRPC = borderline resectable pancreatic cancer
CECT = contrast-enhanced computed tomography
cGy = centigray
CTV = clinical target volume
FOLFIRINOX = 5-FU, leucovorin, irinotecan, oxaliplatin
GTV = gross tumor volume
IMRT = intensity-modulated radiation therapy
ITV = internal target volume
KQ = key question
LAPC = locally advanced pancreatic cancer
L-R = left-right
NK-1 = neurokinin-1
OAR = organs at risk
OS = overall survival
PPP = pancreatic parenchymal phase
PTV = planning target volume
PVP = portal venous phase
RCT = randomized controlled trial
RO = radiation oncologist
RT = radiation therapy
RTOG = Radiation Therapy Oncology Group
SBRT = stereotactic body radiation therapy
S-I = superior-inferior
SIB = simultaneous integrated boost
VMAT = volumetric-modulated arc therapy
41
Appendix 3. Selected Studies Supporting Recommendations

Appendix Table 1. Select institutional and prospective studies for locally advanced pancreatic cancer (KQ1 and KQ2)
Concurrent
Author Dose Dose/fraction Outcomes* Toxicities
chemotherapy
Ben-Josef, 5500 cGy 220 cGy Gemcitabine 1000 Median OS 14.8 mo 24% severe toxicity
201258 mg/m2 FFLP 59% (2)
Huguet, 201771 5600 cGy 200 cGy Gemcitabine, Infusional Median OS 23 mo 4.5% grade 3-4 non-hematologic toxicity
5-FU, or Capecitabine LF 36% (2)
Hurt, 201772 5040 cGy 180 cGy Gemcitabine or Median OS 12.2 mo 11.8% grade 3-4 non-hematologic toxicity
Capecitabine (capecitabine)
Loehrer, 201161 5040 cGy 180 cGy Gemcitabine 600 mg/m2 Median OS 11.1 mo 79% grade 3-4 toxicity (gemcitabine-RT)
Brade, 2007139 5250 cGy 175 cGy Gemcitabine 40 mg/m2 Median OS 13.9 mo 48% grade 3-4 toxicity (excluding
biweekly leukopenia/lymphopenia)
Youl, 201473 5250 cGy 175 cGy Gemcitabine 40 mg/m2 Median OS 12.7 mo Not reported
biweekly
Chauffert, 6000 cGy 200 cGy 5-FU and Cisplatin Median OS 8.6 mo 43.6% grade 3-4 non-hematologic toxicity
200862
Hammel, 201657 5400 cGy 180 cGy Capecitabine 800 Median OS 15.2 mo 23% grade 3-4 non-hematologic toxicity
mg/m2 twice a day
FFLP = freedom from local progression; LF = local failure; OS = overall survival; RT = radiation therapy.
*
Numbers in parentheses represent actuarial rates in years.
42
Appendix Table 2. Select studies of SBRT for non-metastatic pancreatic cancer from 2007-2017 (KQ2)
Reference Stage Number of pts Methods Outcomes Toxicities

Chuong, 201375 BRPC 73 Retrospective: Median dose 2500 cGy in 5 1. 56.1% of BRPC pts completed surgery with 5.3% late grade >3
LAPC fx to tumor with SIB of 3500 cGy to vessel R0 resection in 96.9%, and MS 19.3 mo
abutment 2. 1 y LC 81% in non-surgical pts
Mellon, 201555 BRPC 159 Retrospective: Median dose 3000 cGy in 5 1. 51% of BRPC pts completed surgery with 7% any grade >3
(updated analysis LAPC (BRPC: 110 fx to tumor with SIB of 4000 cGy to vessel R0 resection in 96.0%, and MS 34.2 mo
of Chuong) LAPC: 49) abutment 2. 1 y LC 78% in non-surgical pts
Rajagopalan, BRPC 105 (12 who Retrospective: 2400 cGy in 1 fx (5 pts), 1. 92% R0 resection rate No grade >3
2013140 LAPC completed surgery 3600 cGy in 6 fx (6 pts), 3000 cGy in 3 fx (1 2. 41.7% pCR or <10% viable tumor
are reviewed) pt) 3. 1 y OS 92%, 2 y OS 64%, 3 y OS 51%
Shaib, 2016141 BRPC 13 Prospective (phase I): 5 fx 1. 8/13 pts completed surgery with 100% R0 DL4 reached without
DL1: 3000 cGy, SIB to 3600 cGy DL2: 3600 resection rate grade >3
cGy, SIB to 4200 cGy DL3: 3600 cGy, SIB to 2. At median follow-up of 18 mo, MS not
4350 cGy DL4: 3600 cGy, SIB to 4500 cGy reached in resected pts
Schellenberg, LAPC 16 Prospective (phase II): 1. MS 11.4 mo 7/15 pts surviving >4 mo
2008142 2500 cGy in 1 fx had late grade >2
CyberKnife
Schellenberg, LAPC 20 Prospective (phase II): 1. MS 11.8 mo 20% late grade >2
2011143 2500 cGy in 1 fx
conventional LINAC
Polistina, 201064 LAPC 23 Prospective (phase II): 1. 82.6% local response No grade >2
3000 cGy in 3 fx 2. MS 10.6 mo
3. 8% became resectable
Goyal, 201265 LAPC 20 Retrospective: 1. Tumor volume decrease of 38% at 6 mo 16% grade 3
2200-3000 cGy in 1-3 fx 2. FFLP 88% at 6 mo, 65% at 12 mo No grade >4
3. OS 89% at 6 mo, 56% at 12 mo
Gurka, 201366 LAPC 11 (10 completed Prospective (pilot): 1. MS 12.2 mo No grade >3
SBRT and follow- 2500 cGy in 5 fx to 75%-83% isodose line
up)
43
Reference Stage Number of pts Methods Outcomes Toxicities

Tozzi, 2013144 LAPC 30 (21 LAPC, 9 Retrospective: 4500 cGy in 6 fx (reduced to 1. FFLP 75% at 2 yrs. in entire group, 96% in No grade >3
local recurrence) 3600 cGy in 5 pts to meet OAR constraints) group that received 4500 cGy
2. MS 11 mo
Mahadevan, LAPC 47 Retrospective: induction gemcitabine and 1. 39 pts without metastatic disease after 9% grade 3
2011145 SBRT 2400-3600 cGy in 3 fx induction gemcitabine
2. MS 20 mo
3. LC 85%
Zhong, 2017146 RPC 8450 (631 with Retrospective: SBRT median dose 4000 cGy 1. OS 20.3% for >400 cGy per fraction versus N/A
BRPC SBRT) in 5 fractions versus 5040 cGy in 28 16.3% for <200 cGy at 2 yrs.
LAPC fractions treated neoadjuvantly or
definitively
Moningi, BRPC 88 Retrospective: SBRT 2500-3300 cGy in 5 1. MS 18.4 mo 3.4% grade >3
201556 LAPC fractions 2. 84% R0 resection rate 5.2% late GI >2
3. FFLP 9.8 mo
Rashid et al BRPC 101 Retrospective: Induction gemcitabine, 1. MS 18 mo (33 mo after resection, 14 mo N/A
2016147 docetaxel and capecitabine followed by without resection)
SBRT (3000-4000 cGy in 5 fractions) 2. 96% R0 resection rate (of 55% of pts who
underwent resection)
Gurka, 201792 BRPC 38 Retrospective: SBRT 2500-3000 cGy in 5 fx 1. MS 14.3 mo 4% late grade >3
LAPC with chemotherapy (primarily gemcitabine) 2. FFLP 9.2 mo.
3. LC 79%
Herman, 201563 LAPC 49 Prospective (multi-institution phase II): 1. FFLP 78% at 1 y 11% late grade >2
induction gemcitabine then SBRT 3300 cGy 2. 8% underwent R0, pN0 resections
in 5 fx, adjuvant gemcitabine until 3. MS 13.9 mo.
progression
cGy = centigray; fx = fraction; BRPC = borderline resectable pancreatic cancer; DL = dose level); FFLP = freedom from local progression; fx = fraction; LAPC = locally
advanced pancreatic cancer; LC = local control; LINAC = linear accelerator; MS = median survival; OS = overall survival; PS = performance status; RPC = resectable pancreatic
cancer; SIB = simultaneous integrated boost.
44
Appendix Table 3. Reported tumor motion in free-breathing patients (KQ4)
Mean (SD) in cm Max in cm

Author, Year Number of Pts Measured in: Details
L-R A-P S-I L-R A-P S-I
(Image Sets)
Campbell, 201795 11 (46) CBCT projections N/A 0.5 0.7 1.4 1.2 1.8 3.6
96
Feng, 2009 17 Cine MRI Shallow breathing Min 0.7 2.0 ~0 1.3 4.2
Goldstein, 2010106 30 (45) 4-D CT N/A 0.3 (0.2) 0.3 (0.2) 0.5 (0.2) 0.7 0.7 1.0
104
Heerkens, 2014 15 Cine MRI N/A 0.3 0.5 1.5 0.5 1.3 3.4
Huguet, 2015100 36 4-D CT N/A 0.3 (0.2) 0.6 (0.3) 1.3 (0.7) 0.9 1.8 2.7
Kishi, 2016148 14 (28) 4-D PET N/A 0.3 0.3 0.9 1.2 0.9 1.8
Knybel, 2014149 20 CyberKnife N/A 0.3 0.4 1.1 1.2 1.2 2.7
(60 sessions) SynchronyTM x-ray
Lens, 201498 18 (18) 4-D CT N/A 0.2 (0.1) 0.3 (0.1) 0.8 (0.3) N/A N/A N/A
18 (401) CBCT projections 0.2 (0.1) 0.2 (0.1) 0.7 (0.3)
Minn, 200999 20 (20) 4-D CT N/A 0.3 0.4 0.9 1.3 0.8 2.9
20 (20) CyberKnife Over 0.6 to 1.8 hrs. 0.2 0.3 0.7 4.1 6.8 4.9
SynchronyTM x-ray
Ohira, 2017150 23 (23) 4-D CT Simulation 0.2 0.2 0.8 N/A N/A N/A
23 (448) CBCT and 4-D CT Treatment 0.2 0.3 1.0
Song, 2010151 16 (16) X-ray simulator N/A 0.2 (0.1) 0.3 (0.1) 0.9 (0.2) 0.3 0.4 1.6
Tai, 2013152 15 4-D CT N/A 0.1 (0.1) 0.2 (0.1) 0.6 (0.3)
Shinoki, 2011103 15 (60) 4-D CT N/A 0.1* 0.2* 1.3* 1.0 0.7 1.3
Taniguchi, 2013153 17 4-D CT N/A 0.2 (0.1)* 0.2 (0.0)* 0.4 (0.1)* 0.6 0.5 2.2
4-D = four-dimensional; A-P = anterior-posterior; CBCT = cone beam computed tomography; cm = centimeter; hrs. = hours; L-R = left-right; MRI = magnetic
resonance imaging; N/A = not available; SD = standard deviation; S-I = superior-inferior.
*
Median rather than mean.
45
Appendix Table 4. Reported margins to account for tumor motion in free-breathing patients (KQ4)
Necessary Motion Margin (cm)
Author, Year Number of Pts Measured in: Geometric Coverage From

Left Right Ant Post Sup Inf
(Image Sets) Goal
Campbell, 11 (46) CBCT projections 95% Registered mean 0.3 0.3 0.4 0.4 0.7 0.7
201795 position
Feng, 200996 17 Cine MRI 99% EE position N/A 1.0 0.4 0.7 2.0
95% 0.8 0.3 0.5 1.4
90% 0.8 0.2 0.4 1.3
th
Goldstein, 30 (45) 4-D CT 95 percentile of motion N/A 0.6 0.7 1.0
2010106 at simulation
Huguet, 2015100 36 4-D CT 100% in 95% of pts N/A 0.7 1.1 2.3
Knybel, 2014149 20 CyberKnife 95% of pts <0.3 cm miss EE position 0.5 0.5 2.0
(60 sessions) SynchronyTM x-ray
Ohira, 2017150 23 (448) CBCT and BIR margin formula* N/A 1.1 1.2 2.5
4-D CT
van der Horst, 13 (300) CBCT 2.5Σ+0.7σ† N/A 1.2 1.1 2.0
2013154
Whitfield, 13 (109) CBCT and 95th percentile of intra- N/A 0.7 1.0 2.1
201297 13 (109) fluoroscopy fraction motion
13 (109) BIR margin formula,* Known mid-respiratory 0.9 1.0 1.8
with daily imaging position
BIR margin formula,* Respiratory position in 1.2 1.5 2.8
with daily imaging planning scan unknown
4-D = four-dimensional; Ant = anterior; BIR = British Institute of Radiology; CBCT = cone beam computed tomography; cm = centimeter; EE = end-expiration; Inf = inferior;
MRI = magnetic resonance imaging; N/A = not available; Post = posterior; Sup = superior.
*
The BIR margin formula includes additional sources of uncertainty beyond just respiratory motion.
†
Margin formula from (van Herk, 2004155).
46
Appendix Table 5. Reported tumor motion with a gating technique (KQ4)
Mean (SD) in cm Max in cm

Author, Year Number of Pts Measured in: Details
(Image Sets)
Campbell, 201795 19 (105) CBCT Motion during simulated 0.3 0.4 0.6 1.2 1.2 0.8
projections 40% duty cycle, from EE
100
Huguet, 2015 36 Single 4-D CT Motion during simulated 0.3 0.2 0.5 0.7 0.6 1.3
40% duty cycle, from EE (0.1) (0.2) (0.4)
Shiinoki, 2011103 15 (60) 4-D CT Interfraction variation at 0.0 0.1 0.0 0.7 1.1 1.0
EE, 2-sided (0.3) (0.4) (0.3)
Interfraction variation at 0.1 0.2 0.1 1.6 1.3 1.5
EI, 2-sided (0.5) (0.4) (0.7)
4-D = four-dimensional; A-P = anterior-posterior; CBCT = cone beam computed tomography; CT = computed tomography; cm = centimeter;
L-R = left-right; pts = patients, S-I = superior-inferior; SD = standard deviation.
Appendix Table 6. Reported margins to account for tumor motion with a gating technique (KQ4)
Necessary Motion Margin (cm)

Author, Year Number of Pts Measured in: Geometric From
(Image Sets) Coverage Goal
Campbell, 201795 19 (105) CBCT projections 95% Mean EE 0.2 0.2 0.2 0.2 0.3 0.3
position
Huguet, 2015100 36 4-D CT 100% in 95% of pts EE position 0.4 0.5 1.2
Shinoki, 2011103 15 (60) 4-D CT 95th percentile of EI position 1.0 0.9 0.9 0.6 1.3 1.3
position variation EE position 0.5 0.6 0.9 0.7 0.5 0.6
4-D = four-dimensional; Ant = anterior; CBCT = cone beam computed tomography; CT = computed tomography; cm = centimeter; EE = end expiration;
EI = end inhalation; Inf = inferior; Post = posterior; pts = patients, Sup = superior.
47
Appendix Table 7. Reported tumor motion with a breath-hold technique (KQ4)
Mean (SD) Variation (cm) Max Variation (cm)

Author, Year Number of Pts Measured Details
(Image Sets) in:
Nakamura, 10 (120) CT EEBH, Inter-fraction 0.0 0.1 0.0 (0.2) 0.5 0.5 0.3
2011101 (0.2) (0.2)
EEBH, Intra-fraction 0.0 0.0 0.0 (0.1) 0.3 0.3 0.3
(0.1) (0.1)
Nakamura, 11 CBCT EEBH, Inter-fraction 0.1 0.1 0.1 (0.3) 0.9 0.8 1.7
2015102 versus bony, 2-sided (0.2) (0.2)
A-P = anterior-posterior; CBCT = cone beam computed tomography; CT = computed tomography; cm = centimeter; EEBH = end expiration
breath hold; L-R = left-right; pts = patients, S-I = superior-inferior; SD = standard deviation.
Appendix Table 8. Reported margins to account for tumor position variation using breath-hold (KQ4)
Necessary Margin (cm)

Author, Year Number of Pts Measured in: Geometric From
(Image Sets) Coverage Goal
Nakamura, 10 (120) CT 95th percentile of EEBH 0.5 0.5 0.5 0.5 0.5 0.5
2011101 variation
Ant = anterior; CT = computed tomography; cm = centimeter; EEBH = end expiration breath hold; Inf = inferior; Post = posterior;
pts = patients, Sup = superior.
48
Appendix Table 9. Reported differences for registering to fiducial markers/surgical stents or bony anatomy (KQ4)
Margin Expansions for Registration

Number of Pts Registration Imaging* Mean 3-D Uncertainty
Author, Year (Image Sets) Surrogate |Δ|† L-R A-P S-I Margin Type‡
Pepin, 2015107 9 (54) Stent CBCT 0.8 cm N/A N/A N/A N/A
156§
Van der Horst, 2014 11 (243) Stent CBCT 0.7 cm 0.7 cm 0.7 cm 1.9 cm van Herk
Van der Horst, 2013154║ 13 (300) Bony CBCT N/A 1.2 cm 1.1 cm 2.0 cm van Herk
157
Packard, 2015 12 (243) Bone MV CBCT 0.9 cm 1.1 cm 1.0 cm 2.0 cm van Herk
Whitfield, 201297 13 (109) Bone CBCT N/A 0.7 cm 0.7 cm 1.2 cm P95
158
Yu, 2016 12 (306/15) Bone Radiograph/ CBCT 0.8 cm 0.8 cm 0.9 cm 2.7 cm P95
A-P = anterior-posterior; CBCT = cone-beam computed tomography; L-R = left-right; MV = megavoltage; N/A = not available; pts = patients, S-I = superior-inferior.
*
All online image data was acquired with a free-breathing technique.
†
Mean 3-D |Δ| refers to the average magnitude of the 3-D difference between registering to fiducials and registering to bone or a stent.
‡
Margin Types: van Herk PTV margin expansions are designed to ensure a minimum of 95% of the prescribed dose is delivered to the target volume in 90% of pts.155
P95 refers to the margin needed to account for 95% of the observed deviations (ie, the 95th percentile).
§
Stent-based alignment outperformed bony registration in 67% of the patient scans.
║
Bony registration differed from fiducial-based alignment by >1.0 cm in 39% of the fractions.
Appendix Table 10. Reported mean HU differences between pancreatic ductal adenocarcinoma and normal
pancreas by CT contrast Phase (KQ4)
Mean HU Difference (Pancreatic Ductal Adenocarcinoma versus

Pancreas) versus Contrast Phase
Author, Year Number of Pts AP PPP PVP DP No CE
McNulty, 2001159 28 16 49 44 N/A N/A
Scialpi, 2014160 38 N/A 38 26 7 7
Godfrey, 2017111 10 21 47 48 8 10
AP = (early) arterial phase, CT = computed tomography; HU = Hounsfield unit, N/A = not available;
PPP = pancreatic parenchymal phase (also known as the late arterial phase), pts = patients, PVP = portal venous phase,
DP = delayed phase, No CE = non-contrast CT.
49
Appendix 4. Literature Search Strategies
Search Limits:
Age Range: Adult (≥18 years old)
Language: English only
Publication Date: 05/01/2007 – 06/05/2017
Publication Types: All
Rationale for abstract exclusion:

1. Recurrent disease
2. Salvage therapy or reirradiation
3. Proton or another type of particle therapy
4. Intraoperative radiation therapy
5. Pediatric patients
6. Pre-clinical data (non-human)
7. Cost effectiveness studies
8. Studies available in abstract only
9. Comment or editorial
10. Otherwise not relevant or out of scope
Patient number thresholds:

• Key Questions 1-3 and 6: 40 patients for conventional fractionation and 20 patients for stereotactic
body radiation therapy
• Key Questions 4-5: 10 patients with pancreatic cancer
• Key Question 7: No restriction
Key Question 1: In patients with pancreatic cancer, what are the appropriate indications for regimens that
include conventionally fractionated radiation therapy or stereotactic body radiation therapy as:
Search terms:
1. "pancreatic neoplasms"[Mesh]
2. “pancreatic cancer”
3. “pancreas cancer”
4. “pancreatic neoplasm”
5. “pancreas neoplasm”
6. "radiotherapy"[Mesh]
7. “radiation”
8. “radiotherapy”
9. “chemoradiotherapy”[Mesh]
10. “chemoradiotherapy”
11. “chemoradiation”
12. “stereotactic”
13. “SBRT”
14. “SABR”
15. “adjuvant”
Online supplements are not copyedited, and the authors are responsible for the accuracy of the data.
16. “post-operative”
17. “postoperative”
18. “neoadjuvant”
19. “pre-operative”
20. “preoperative”
21. “definitive”
22. “primary”
23. “curative”
PubMed search strategy:

1. "pancreatic neoplasms"[Mesh] OR “pancreatic cancer” OR “pancreas cancer” OR “pancreatic neoplasm”
OR “pancreas neoplasm”
2. “stereotactic” OR “SBRT” OR “SABR”
3. “chemoradiotherapy”[Mesh] OR “chemoradiotherapy” OR “chemoradiation”
4. “concurrent” OR “concomitant”
5. “adjuvant” OR “post-operative” OR “postoperative” OR “neoadjuvant” OR “pre-operative” OR
“preoperative” OR “definitive” OR “primary” OR “curative”
6. 3 AND 4
7. 2 OR 6
8. 1 AND 5 AND 7
Total articles retrieved: 202 with date and language filters
Key Question 2: In patients with pancreatic cancer receiving radiation therapy, what are the appropriate
dose-fractionation schemes and target volumes for:
• Conventionally fractionated radiation therapy and chemotherapy?
• Stereotactic body radiation therapy?
Search terms:
10. “SBRT”
11. “SABR”
12. “fractionation”
13. “target volume”
14. “CTV”
15. “PTV”

51
2. “chemoradiotherapy”[Mesh] OR “chemoradiotherapy” OR “chemoradiation” OR “stereotactic” OR

“SBRT” OR “SABR”
3. “fractionation” OR “target volume” OR “CTV” OR “PTV”
4. 1 AND 2 AND 3
Key Question 3: In patients with pancreatic cancer receiving radiation therapy, what is the appropriate
sequencing of chemotherapy with radiation as:
Search terms:
7. “radiation”
12. “sequence”
13. “sequencing”
14. “order”
15. “interval”
16. “timing”

1. “pancreatic neoplasms"[Mesh] OR “pancreatic cancer” OR “pancreas cancer” OR “pancreatic neoplasm”
2. “radiotherapy"[Mesh] OR “radiation” OR “radiotherapy”
4. “sequence” OR “sequencing” OR “order” OR “interval” OR “timing”
5. 2 AND 3
6. 1 AND 4 AND 5
Key Question 4: In patients with pancreatic cancer receiving radiation therapy, how do the following impact
target and normal tissue delineation, treatment planning techniques, and treatment delivery accuracy for
conventionally fractionated radiation therapy and stereotactic body radiation therapy:
• Motion management?
• Image guidance?
• Contrast administration during CT simulation?
52
Search terms:
7. “radiation”
13. “SBRT”
14. “SABR”
15. “simulation”
16. “immobilization”
17. “motion management”
18. “contrast media”
19. “contrast agent”
20. “contrast material”
21. “contrast enhanced”
22. “fiducial”

2. "radiotherapy"[Mesh] OR “radiation” OR “radiotherapy” OR “stereotactic” OR “SBRT” OR “SABR”
3. “simulation” OR “immobilization” OR “motion management” OR “contrast media” OR “contrast agent”
OR “contrast material” OR “contrast enhanced” OR “fiducial”
4. 1 AND 2 AND 3
Key Question 5: In patients with pancreatic cancer receiving radiation therapy, how do different treatment
planning techniques (3-D conformal radiation therapy, intensity-modulated radiation therapy, volumetric-
modulated arc therapy) impact treatment delivery and dose to organs at risk?
Search terms:
7. “radiation”
9. “3D”
53
10. “intensity-modulated”
11. “IMRT”
12. “volumetric”
13. “arc”
14. “VMAT”
15. “treatment planning”
16. “treatment delivery”
17. “normal tissue”
18. “organs at risk”
19. “dose constraints”
20. “dose limits”

2. "radiotherapy"[Mesh] OR “radiation” OR “radiotherapy”
3. “3D conformal” OR “intensity-modulated” OR “IMRT” OR “volumetric” OR “arc” OR “VMAT”
4. “planning” OR “delivery” OR “normal tissue” OR “organs at risk” OR “dose constraints” OR “dose limits”
5. 2 AND 3
6. 1 AND 4 AND 5
Key Question 6: In patients with metastatic pancreatic cancer, what are the appropriate indications for
radiation in palliative therapy?
Search terms:
7. “radiation”
12. “palliative”

4. 2 AND 3
5. 4 AND “palliative”
6. 1 AND 5
54
Key Question 7: In patients with pancreatic cancer receiving radiation therapy, how do prophylactic
medications impact the incidence and severity of acute and late toxicities?
Search terms:
1. “cancer”
2. “carcinoma”
4. “radiation”
6. "radiation-induced nausea and vomiting"
7. "proton pump inhibitor"
8. "PPI"
9. "pneumococcal"
10. "5-Hydroxytryptamine-3”
11. "5-HT3"
12. "granisetron"
13. "ondansetron"
14. "dolasetron"
15. "tropisetron"
16. "anti-emetic"
17. “antiemetic”

1. “cancer” OR “carcinoma”
3. "radiation-induced nausea and vomiting" OR "proton pump inhibitor" OR "PPI" OR "pneumococcal" OR
"5-Hydroxytryptamine-3" OR "5-HT3" OR "granisetron" OR "ondansetron" OR "dolasetron" OR
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Palta et al ASTRO RT for Pancreatic Cancer Guideline Practical Radiation Oncology

Practical Radiation Oncology (2019)

Radiation Therapy for Pancreatic Cancer: An

Manisha Palta, MD,a* Devon Godfrey, PhD,a Karyn A. Goodman, MD,b

a. Duke University, Durham, North Carolina, Department of Radiation Oncology

Task Force Members’ Disclosure Statements

Table 1. ASTRO recommendation grading classification system

Strength of Overall Quality of Recommendation

2.2. Document Review and Approval

2.3. Evidence Review

2.4. Scope of the Guideline

Table 2. KQs in Population, Intervention, Comparator, Outcome (PICO) format

KQ Population Intervention Comparator Outcomes

3. Key Questions and Recommendations

See Table E1 for the evidence supporting the recommendations.

Table 3. Recommendations for indications for conventionally fractionated RT or SBRT

3.2. Key Question 2: Dose-fractionation and target volumes

Table 4. Recommendations for dose-fractionation and target volumes

Implementation Remark: A number of fractionation schemes

Implementation Remark: SBRT does not routinely treat

Implementation Remark: SBRT does not routinely treat

Table 5. Normal tissue dose constraints for conventionally fractionated RT

Structure RTOG 0848 QUANTEC

Table 6. Normal tissue dose constraints for SBRT

Structure Dose Constraints*

V2000 cGy <3cc

3.3. Key Question 3: Sequencing of chemotherapy and RT

See Table E1 for the evidence supporting the recommendations.

Table 7. Recommendations for sequencing of chemotherapy and RT in patients receiving RT

3.4. Key Question 4: Simulation considerations

See Table E2 for the evidence supporting the recommendations.

Table 8. Recommendations for simulation consideration

Implementation Remark: For palliative or postoperative RT,

Implementation Remarks: Conditional Moderate 100%*

guidance, to confirm that the ITV adequately accounts for

Contrast Administration During CT Simulation

3.5. Key Question 5: Treatment planning techniques

See Table E2 for the evidence supporting the recommendation.

Table 9. Recommendation for treatment planning

3.6. Key Question 6: Indications for palliative RT

See Table E1 for the evidence supporting the recommendation.

Table 10. Recommendation for palliative RT

3.7. Key Question 7: Prophylactic medications for toxicity

See Table E3 for the evidence supporting the recommendations.

Table 11. Recommendations for prophylactic medications for toxicity

Survey Question Yes No

4. Emerging Data/Future Directions

Figure 1. PRISMA Diagram

Records identified through Additional records identified

Records after duplicates removed

Abstracts assessed for

PRISMA = Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Appendix 1. Peer Reviewers and Disclosures (Comprehensive)

Appendix 3. Selected Studies Supporting Recommendations

Reference Stage Number of pts Methods Outcomes Toxicities

Reference Stage Number of pts Methods Outcomes Toxicities

Appendix Table 3. Reported tumor motion in free-breathing patients (KQ4)

Mean (SD) in cm Max in cm

Necessary Motion Margin (cm)

Author, Year Number of Pts Measured in: Geometric Coverage From

Appendix Table 5. Reported tumor motion with a gating technique (KQ4)